Enhancing PARP inhibitor efficacy in ovarian cancer: targeting the PI3K/AKT/mTOR pathway.

DNA damage is a common occurrence in cellular life, arising spontaneously from metabolic processes or induced by external factors such as radiation, chemical modifications, replicative stress, enzymatic reactions, or genotoxic agents. These insults primarily manifest as SSBs or the more severe double-strand breaks (DSBs), which, if unrepaired, can disrupt transcription and genome replication, potentially leading to cell death [ 69 ]. To counteract these threats, cells employ a sophisticated DNA damage response (DDR) system, a network of signaling pathways that coordinates cell cycle arrest, replication fork regulation, and DNA repair to prevent damage propagation to daughter cells. Six primary DNA repair pathways address SSBs and DSBs, each tailored to specific types of lesions. SSBs, the most frequent DNA lesions, are typically resolved through excision repair mechanisms, including BER, nucleotide excision repair, mismatch repair (MMR), and translesional synthesis. These pathways ensure precise restoration of single-strand integrity, preventing their escalation into DSBs [ 70 ]. DSBs, critical threats to genomic integrity, are repaired mainly via HR or non-homologous end joining (NHEJ), with alternative end joining as a secondary mechanism [ 71 ]. HR, an accurate repair process, functions in the S and G2 cell cycle phases, using sister chromatids for precise repair, driven by the MRE11-RAD50-NBS1 complex, ATM, and ATR kinase to pause the cell cycle. Conversely, NHEJ, a rapid but error-prone pathway, is active throughout the cell cycle except M phase, predominantly in G1. It involves Ku70/80, DNA-PKcs, Artemis, DNA polymerases λ/μ, DNA ligase IV-XRCC4, XLF, and newer proteins like PAXX, MRI/CYREN, TARDBP, IFFO1, ERCC6L2, and RNase H2. MRI/CYREN promotes NHEJ in G1 but inhibits it in S/G2 [ 72 , 73 ]. This dynamic interplay is vital in ovarian cancer, where targeting HR deficiencies boosts PARP inhibitor efficacy [ 74 ]. Homologous recombination operates during the S and G2 phases of the cell cycle, leveraging a sister chromatid as a template to achieve error-free repair. This process involves the Meiotic Recombination 11-Like (MRE11) nuclease, which forms a complex with RAD50 and NBS1 (Nijmegen Breakage Syndrome 1). This complex recruits ATM and activates the RAD3-related ATR kinase, halting the cell cycle and generating 3'-single-stranded DNA (ssDNA) ends. Replication Protein A (RPA) coats these ssDNA ends, which are subsequently replaced by RAD51, forming nucleoprotein filaments critical for homology search and strand exchange with the sister chromatid [ 75 , 76 ]. Conversely, NHEJ, which predominates in the G1 phase but occurs throughout the cell cycle, is faster but error-prone. In NHEJ, the Ku70/80 heterodimer recognizes and binds DSB ends, recruiting the DNA-PK catalytic subunit to form a multi-unit complex. Additional proteins, such as Artemis and PNK, facilitate processing, while polymerases and ligases restore DNA integrity by binding and sealing the broken ends [ 77 ]. The DDR pathways' therapeutic relevance is particularly evident in the context of ovarian cancer, where targeting DNA repair mechanisms has emerged as a promising strategy. PARP inhibitors exploit synthetic lethality in cells with BRCA mutations, which impair HR repair. By blocking SSB repair, PARP inhibitors promote the formation of DSBs, which BRCA-deficient cells cannot effectively repair, leading to apoptosis. Beyond inhibiting PARP enzymatic activity, these inhibitors trap PARP1 on damaged DNA, stalling replication forks and exacerbating DSB formation. However, the clinical efficacy of PARP inhibitors hinges on their PARP-trapping efficiency, and mutations in PARP1 that reduce trapping can confer drug resistance [ 78 ]. This interplay between DNA repair pathways and therapeutic interventions underscores the potential for combining PARP inhibitors with other targeted therapies, such as those modulating the PI3K/AKT/mTOR pathway, to enhance treatment outcomes in ovarian cancer.

PARPs constitute a family of 17 proteins that are integral to various cellular processes, including DNA repair, chromatin remodeling, stress response, and programmed cell death. Among these, PARP-1 is particularly significant due to its pivotal role in DNA repair mechanisms [ 79 ]. Structurally, PARP-1 comprises three key domains: an N-terminal DNA-binding domain featuring zinc finger motifs, a central auto-modification domain that facilitates the protein’s dissociation from DNA post-catalysis, and a C-terminal catalytic domain (CAT) that encompasses the enzymatic activity and binding sites for nicotinamide adenine dinucleotide (NAD +). SSBs typically arise from oxidative stress, whereas DSBs are often induced by chemical or physical insults [ 80 ]. The repair processes for both SSBs and DSBs are intricately linked to the functions of PARP enzymes. PARP enzymes, particularly PARP-1, are pivotal in maintaining genomic integrity through their involvement in multiple DNA repair pathways. PARP-1, the most extensively studied member of the 17- or 18-member PARP family, is critical for SSB repair and BER, accounting for approximately 90% of total PARP activity [ 81 , 82 ]. Its enzymatic function involves catalyzing the addition of ADP-ribose units to substrate proteins, including itself, using NAD + as a cofactor, a process known as PARylation. This activity is triggered by DSBs, enabling PARP to recruit essential repair proteins to damage sites, a mechanism that has garnered significant attention in both biological and biophysical research [ 83 ]. The PARylation process begins when PARP-1, in its unbound state, detects DNA damage via its zinc finger structures. Upon binding to SSBs, PARP-1 utilizes NAD + to transfer ADP-ribose or poly (ADP-ribose) (PAR) chains to itself and other acceptor proteins, such as DNA ligase III, DNA polymerase β, and the scaffold protein XRCC1. These proteins form a molecular framework that facilitates DNA repair by branching PAR polymers at damage sites. Once repair is complete, molecular changes reduce PARP-1’s affinity for DNA, leading to its release and return to an unbound state, ready to sense further damage [ 84 ]. This dynamic binding and unbinding cycle underscores PARP-1’s role as a ribozyme in orchestrating efficient SSB repair. Beyond SSB and BER, emerging evidence highlights PARP’s broader influence in DSB repair pathways, including HR and microhomology-mediated end-joining (MMEJ). In HR, PARP-1 recruits critical enzymes such as MRE11 and NBS1 and regulates the expression of key genes like BRCA1 and RAD51 at the transcriptional level [ 72 ]. As illustrated in Fig.  2 , in MMEJ, a distinct DSB repair pathway that relies on microhomology sequences flanking break sites, PARP-1 collaborates with DNA polymerase theta (POLQ). POLQ is recruited to damage sites in a PARP-dependent manner, distinguishing MMEJ from the classical NHEJ pathway [ 73 ]. This multifaceted role of PARP in both SSB and DSB repair pathways underscores its significance in DNA damage response and nucleosome remodeling. Fig. 2 Multifaceted Role of PARP in DNA Damage Repair Pathways. This schematic illustrates the central role of PARP, particularly PARP-1, in sensing and repairing DNA damage. ( 1 ) Upon SSBs, PARP-1 is recruited to the damage site, where it catalyzes PARylation using NAD⁺, facilitating the recruitment of repair proteins such as XRCC1, DNA ligase III, and polymerase β to complete BER. ( 2 ) Inhibition of PARP leads to the persistence of SSBs, which collapse into DSBs during replication. Cells proficient in HR can survive by repairing these DSBs, while HR-deficient cells accumulate genomic instability, leading to cell death. ( 3 ) PARP also participates in MMEJ, a backup DSB repair pathway. Upon DSBs, PARP facilitates end resection and annealing, followed by flap cleavage (via XPF/ERCC1), and final gap filling and ligation (by XRCC1, DNA ligase, and POLQ). Collectively, these processes underscore PARP's essential role in preserving genomic stability and its therapeutic relevance in targeting HR-deficient cancers Multifaceted Role of PARP in DNA Damage Repair Pathways. This schematic illustrates the central role of PARP, particularly PARP-1, in sensing and repairing DNA damage. ( 1 ) Upon SSBs, PARP-1 is recruited to the damage site, where it catalyzes PARylation using NAD⁺, facilitating the recruitment of repair proteins such as XRCC1, DNA ligase III, and polymerase β to complete BER. ( 2 ) Inhibition of PARP leads to the persistence of SSBs, which collapse into DSBs during replication. Cells proficient in HR can survive by repairing these DSBs, while HR-deficient cells accumulate genomic instability, leading to cell death. ( 3 ) PARP also participates in MMEJ, a backup DSB repair pathway. Upon DSBs, PARP facilitates end resection and annealing, followed by flap cleavage (via XPF/ERCC1), and final gap filling and ligation (by XRCC1, DNA ligase, and POLQ). Collectively, these processes underscore PARP's essential role in preserving genomic stability and its therapeutic relevance in targeting HR-deficient cancers The critical functions of PARP in DNA repair make it a prime target for therapeutic intervention, particularly in cancers like epithelial ovarian cancer, where DNA repair pathways are often defective. Cancer cells with deficiencies in one repair pathway, such as HR, become reliant on alternative pathways like PARP-mediated repair. Inhibiting PARP in these cells can induce synthetic lethality, a strategy that exploits this dependency to selectively kill cancer cells [ 85 ]. PARP inhibitors, by disrupting PARylation and trapping PARP at DNA damage sites, prevent the recruitment of repair proteins, leading to replication fork collapse and DSB accumulation. The interplay between PARP and repair proteins like XRCC1, DNA ligase I, and POLQ further amplifies the impact of these inhibitors, transforming the treatment landscape for epithelial ovarian cancer and highlighting the intricate connection between PARP’s molecular functions and clinical outcomes [ 86 ]. PARP inhibitors are critical therapeutic agents in the treatment of ovarian cancer, particularly for tumors with BRCA1/2 mutations that impair homologous recombination repair (HRR). First identified in 2005 for their synthetic lethal interaction with BRCA-deficient cells, these inhibitors target DNA repair pathways to induce cancer cell death. By blocking the repair of SSBs, PARP inhibitors cause these lesions to persist, potentially converting into double-strand DNA breaks (DSBs) during DNA replication. In cells lacking functional BRCA1/2, the inability to repair DSBs via HRR leads to apoptosis [ 87 ]. However, some research disputes the direct link between SSB-to-DSB conversion and cell death, as PARP inhibition does not significantly increase SSB levels in either wild-type or BRCA-deficient cells, and DSB accumulation post-treatment is minimal. Nonetheless, it is widely agreed that PARP inhibitors disrupt an alternative DNA repair pathway, creating synthetic lethality in HR-deficient cancer cells [ 88 ]. A key mechanism of PARP inhibitors is their ability to trap PARP enzymes on DNA at sites of damage. By binding to the NAD + catalytic site, inhibitors like talazoparib prevent PARP dissociation, forming stable PARP-DNA complexes that disrupt replication forks. This replication fork collapse generates cytotoxic DSBs, which are particularly lethal in HR-deficient ovarian cancer cells, as these cells cannot effectively repair the damage, unlike cells with intact HRR pathways [ 89 ]. The effectiveness of PARP inhibitors varies; for example, olaparib primarily inhibits PARP’s enzymatic activity by binding its active site, while talazoparib excels at trapping PARP, enhancing cytotoxicity. Selecting the appropriate inhibitor based on a patient’s genetic profile is crucial for optimizing treatment outcomes [ 90 ]. PARP inhibitors also modulate NHEJ, a faster but error-prone DSB repair pathway active throughout the cell cycle. NHEJ involves proteins like Ku70/80, DNA-PKcs, and newly identified factors such as PAXX and MRI/CYREN, with the latter promoting NHEJ in G1 but inhibiting it in S and G2 phases. Normally, PARP-1 suppresses NHEJ by modifying Ku70/80 and DNA-PKcs through PARylation, but PARP inhibitors relieve this suppression, promoting error-prone repair that increases genomic instability and cell death [ 91 , 92 ]. The extent to which NHEJ contributes to synthetic lethality remains under study, emphasizing the need for tailored therapies based on individual genetic mutations. By inhibiting PARP’s catalytic activity and preventing PAR polymer formation, PARP inhibitors impair the base excision repair (BER) pathway, essential for SSB repair. In cells with functional HR and BER, or HR-deficient but BER-intact cells, viability is preserved. However, in HR-deficient cells treated with PARP inhibitors, the simultaneous loss of BER and HR forces reliance on NHEJ, leading to lethal genomic instability. This synthetic lethality underpins the success of PARP inhibitors like olaparib and niraparib, which are FDA-approved for maintenance therapy in HGSOC post-platinum chemotherapy [ 93 ]. The varying trapping efficiencies, with talazoparib being the most potent, highlight their tailored cytotoxicity in BRCA-mutated tumors. The multifaceted action of PARP inhibitors, disrupting BER, trapping PARP, and altering NHEJ, makes them a powerful tool for exploiting DNA repair deficiencies in ovarian cancer. Their ability to induce synthetic lethality by targeting multiple repair pathways underscores their therapeutic potential. As research advances, combining PARP inhibitors with other targeted therapies, such as PI3K/AKT/mTOR pathway inhibitors, may further enhance their efficacy, offering new hope for personalized ovarian cancer treatment. Over the past decade, PARP inhibitors have undergone extensive investigation in both preclinical and clinical settings, yielding highly encouraging outcomes. These results have been particularly transformative for ovarian cancer management, with clinical trial data suggesting a significant shift in treatment paradigms. Consequently, the U.S. Food and Drug Administration (FDA) has approved three PARP inhibitors for ovarian cancer treatment: Olaparib, Rucaparib, and Niraparib [ 94 ]. An updated overview of clinical and preclinical studies investigating PARP inhibitors in ovarian cancer is presented in Table  3 of this review, with further discussion of each inhibitor provided below. Table 3 Combination strategies involving PARP inhibitors in ovarian cancer: preclinical and clinical outcomes Regulator or combination drug Dosage of combination PARP inhibitor and dosage Ovarian cancer cell lines, tissue or participants Type of study Targtes Effects Ref Olaparib Cisplatin + paclitaxel Cisplatin: 0.0625x–2.0 × IC50 (13.87 ± 0.08 µM for A2780, 14.93 ± 0.07 µM for OVCAR-3); Paclitaxel: 0.0625x–2.0 × IC50 (5.54 ± 0.21 µM for A2780, 7.64 ± 0.14 µM for OVCAR-3) Olaparib (0.0625x–2.0 × IC50; 6.00 ± 0.35 µM for A2780, 12.21 ± 0.10 µM for OVCAR-3) A2780 and OVCAR-3 cell lines Preclinical, In vitro ↓Proliferation, ↑Apoptosis, Synergistic effects [ 95 ] Topotecan-loaded liposomes (TLL) 0.001–25 μM in vitro; OLL: 0.0016–1.6 mM in vitro Olaparib (loaded in liposomes, 0.0016–1.6 mM in vitro) HEOC, EOC 1–4 (clear-cell tumors), malignant ascites, OCI-E1p endometrioid primary ovarian cancer cell line Preclinical, In vitro Topoisomerase I ↓Proliferation, ↑Cytotoxicity, Synergistic antitumor effect [ 96 ] Cellular retinoic acid-binding protein 2 (CRABP2) Not specified Olaparib (50 mg/kg, intraperitoneally (i.p.), every other day for 14 in vivo; 0, 0.05, 0.1, and 0.2 μM/ml in vitro) OVCAR3 and TOV112D Female BALB/C-nu/nu mice Preclinical In vitro and in vivo Caspase-8/ROS ↓Olaparib sensitivity ↑Proliferation [ 97 ] AZD7648 (DNA-PK inhibitor) Not specified Olaparib (orally, dose not specified) Patient-derived ovarian cancer xenografts (OC-PDX), subcutaneous and orthotopic in peritoneal cavity Preclinical, In vitro and in vivo pDNA-PKcs, pRPA32, γH2AX ↓Tumor growth, ↓Abdominal metastatic dissemination, ↑Lifespan in orthotopic models, ↑Olaparib efficacy in BRCA-deficient OCcию [ 98 ] Selinexor (selective inhibitors of nuclear export) Not specified Olaparib (dose not specified) A2780luc, OVCAR5 cell lines, Female mice (A2780luc ip1 and OVCAR5 models) Preclinical, In vitro and in vivo DNA damage repair ↓Tumor weight, ↓Tumor nodules, ↓DNA damage repair protein expression, ↑Tumor suppressor protein expression [ 99 ] Sodium bicarbonate 4 g/L (A2780), 7 g/L (SKOV3) in vitro; 5 mg/kg i.p. in vivo Olaparib (20 μM (A2780), 40 μM (SKOV3) in vitro; 5 mg/kg i.p. in vivo) A2780, SKOV3 cell lines, Female C57BL/6 mice with ID8-luc ovarian cancer cells Preclinical, In vitro and in vivo cGMP/PKG, ROS, M1 macrophage ↓Proliferation, ↑Apoptosis, ↓Migration, ↓Invasion, ↓ROS, ↑M1 macrophage infiltration [ 100 ] iFSP1 (FSP1 inhibitor) 2 mg/kg/d in vivo; 10–25 μM in vitro Olaparib (50 mg/kg/d in vivo; 10–20 μM in vitro) HO-8910, A2780, SKOV3, OVCAR3 cell lines, 10 patient-derived organoids (PDOs) from BRCA-proficient patients, Female BALB/c mice Preclinical, In vitro and in vivo NHEJ, Ku70 PARylation ↓Proliferation, ↑Apoptosis [ 101 ] Ubiquitin-conjugating enzyme E2S (UBE2S) PCMV-UBE2S, PCMV-UBE2S-C95S, UBE2S shRNAs; XAV-939 (10 μM in vitro, 15 mg/kg i.p. in vivo) Olaparib (15 μM for A2780, 30 μM for SKOV3 in vitro; 20 mg/kg i.p. daily in vivo) A2780, SKOV3 cell lines, 120 HGSOC tissues, 21 fallopian tube tissues, Male BALB/c nude mice Preclinical, In vitro and in vivo, Wnt/β-catenin, APC/C ↑Proliferation, ↑Migration, ↑Invasion, ↑Olaparib resistance, ↓Apoptosis [ 102 ] CDCA8 (silencing) + MYBL2 Not specified Olaparib (25 μM for A2780, 100 μM for SKOV3 in vitro; cisplatin 2 μg/ml in vitro) A2780, SKOV3, HEY cell lines, HGSOC tissues, Female BALB/c nude mice Preclinical, In vitro and in vivo p53 signaling, MYBL2-CDCA8 ↓Proliferation, ↓Migration, ↓Invasion, ↑Apoptosis, ↑G2/M arrest, ↑DNA damage, ↑Sensitivity to olaparib and cisplatin [ 103 ] Dasatinib (kinase inhibitor) + Quercetin Dasatinib: 5 mg/kg, Quercetin: 50 mg/kg, Carboplatin: 2 mg/kg, i.p., 3 times/week for 4 weeks Olaparib (50 mg/kg, i.p., 3 times/week for 4 weeks) OVCAR3, ID8-Luc2, Female C57BL/6J mice, Human ADSCs Preclinical, In vitro and in vivo Inflammatory cytokines, Chemokines, NF-κB pathway ↓Peritoneal and adipose tissue metastasis, ↓Adipose tissue aging, ↑Glucose homeostasis, ↓Proliferation, ↓Migration, ↑Chemosensitivity [ 104 ] ceralasertib)ATR inhibitor(or MK-8776)CHK1 inhibitor( ATRi: 25 mg/kg, oral, 5 days/week, CHK1i: 50 mg/kg, i.p., twice/week Olaparib (50 mg/kg, i.p., 5 days/week) PDX-X179 (BRCA1/2MUT HGSOC from treatment-naïve patients), NSG/J female mice Preclinical, In vivo ATR/CHK1, PARP ↓DDR ↓EMT [ 105 ] Olaparib 47 patient-derived xenografts Preclinical, In vivo RAD51 foci, HRDetect, BRCA1/2 mutations, BRCA1 promoter methylation ↓RAD51 foci score correlates with ↑olaparib sensitivity, associates with platinum activity [ 106 ] Panobinostat (Histone deacetylase (HDAC) inhibitors) 2.5 mg/kg, i.p., 5 times weekly in vivo; 25 nM in vitro Olaparib (100 mg/kg, oral, 5 times weekly in vivo; 10 μM in vitro) SKOV-3, ID8-luc cell lines, C57BL/6 female mice Preclinical, In vitro and in vivo HR repair, immune response ↓HR gene expression, ↓Proliferation, ↑Apoptosis, ↑DNA damage, ↑CD8 + T cell infiltration, ↓M2-like macrophage markers [ 107 ] Bevacizumab + durvalumab 15 mg/kg intravenously, once-every-3-weeks + 1.12 g intravenously, once-every-3-weeks Olaparib (300 mg orally, twice daily) 74 patients, 41 of whom had platinum-resistant relapse and 33 had platinum-sensitive relapse Phase II clinical trial ↓Olaparib sensitivity, ↑Proliferation [ 108 ] Olaparib (300 mg orally, twice daily) 225 patients with platinum-sensitive relapsed ovarian cancer (PSROC), mainly Chinese, from 28 centres in China and Malaysia Phase III clinical trial “HRD-positive patients had prolonged median PFS (17.9 months vs. 9.2 months for HRD-negative). Positive PD-L1 expression associated with decreased olaparib efficacy in gBRCAm patients (14.5 months vs. 22.2 months) but improved efficacy in BRCAwt patients (20.9 months vs. 8.3 months).” [ 109 ] cediranib Cediranib: 20 mg once daily Olaparib (300 mg twice daily) 139 patients with ovarian, fallopian tube, or primary peritoneal cancer relapsed within 12 months of platinum therapy (90% platinum-resistant), 30% with germline BRCA1/2 mutations Phase II clinical trial ↑PFS for olaparib + cediranib (5.4 mo) vs olaparib (3.7 mo), manageable toxicity (e.g., 4% Grade 3 diarrhoea, 4% Grade 3 hypertension in olaparib + cediranib) [ 110 ] Olaparib (300 mg tablets, orally, twice daily 147 patients with BRCA1/2-mutated platinum-sensitive relapsed ovarian cancer (69 placebo, 78 olaparib) Phase III clinical trial ↓Efficacy of platinum-based chemotherapy post-olaparib [ 111 ] Olaparib (300 mg orally, twice daily) 391 patients with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation (260 olaparib, 131 placebo) Phase III clinical trial Median PFS 56 vs 14 months (olaparib vs placebo); 42% vs 17% progression-free at 5 years in higher-risk subgroup; 56% vs 25% in lower-risk subgroup; 63% reduced risk of disease recurrence or death in complete response patients [ 112 ] Olaparib 400 mg (capsules) twice daily 177 patients with platinum-sensitive relapsed ovarian cancer (PSR OC) with gBRCAm, sBRCAm, or non-BRCA HRRm Phase IV clinical trial BRCA1/2, HRR pathway Median OS: 46.8 months (BRCAm), 43.2 months (sBRCAm), 47.4 months (gBRCAm), 44.9 months (non-BRCA HRRm); consistent clinical activity across cohorts [ 113 ] Rucaparib 10058F4 (MYC inhibitor) Not specified Rucaparib In vitro OC model with 8q24 copy number increase Preclinical, In vitro MYC/PVT1, PARP10, FAM83H ↓Proliferation, ↑Apoptosis [ 114 ] Nutlin-3/RG7388 Nutlin-3: 1.76 ± 0.51 μM in vitro; RG7388: 253.3 ± 73.1 nM in vitro Rucaparib (0.4–25 μM in vitro) A2780, IGROV-1, OAW42, CP70, MLH1-corrected CP70 +, MDAH-2774, SKOV-3 Preclinical, In vitro p53 ↓Proliferation, ↑Cell cycle arrest (G2/M), ↑Apoptosis [ 115 ] Rucaparib (varying concentration) SKOV3, A2780, and IOSE80 Preclinical, In vitro RIP1/RIP3, ROS ↓Proliferation, ↑Necrotic apoptosis [ 116 ] RMP1-14 (PD-1 antibody) + 10F.9G2 (PD-L1 antibody) PD-1: 5–10 mg/kg, i.p., twice weekly; PD-L1: 5–10 mg/kg, i.p., twice weekly Rucaparib (150 mg/kg, oral, twice daily) BRCA1 mutant BrKras (BRCA1-/-; P53-/-; myc; Kras-G12D; Akt-myr) and BRCA1 wild-type C2Km (P53-/-, myc, Kras-G12D, Akt-myr) murine ovarian cell lines, FVB/N mice Preclinical, In vitro and in vivo BRCA1 mutation, PD-1/PD-L1 ↑Survival, ↑Tumor growth inhibition [ 117 ] Bevacizumab (VEGF/VEGFR inhibitor) 15 mg/kg intravenously, once-every-3-weeks Rucaparib (400 mg, 500 mg, or 600 mg twice daily) 9 patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer Phase I clinical trial Maximum tolerated dose of rucaparib is 500 mg twice daily when combined with bevacizumab; no new safety concerns; no pharmacokinetic interactions [ 118 ] Atezolizumab (PD-L1 inhibitor) Atezolizumab: 1200 mg intravenously, Day 1 every 3 weeks Rucaparib (600 mg orally, twice daily) Patients with advanced gynaecological or triple-negative breast cancer (tBRCAmut or tBRCAwt/LOHhigh) Phase Ib clinical trial PD-L1, CD8 + T-cell activity, cGAS-STING ↓DDR, ↓Cell cycle, ↑Apoptosis, ↑CD8 + T-cell activity, [ 119 ] Rucaparib (40–500 mg once daily, 240–840 mg twice daily in phase I; 600 mg twice daily in phase II) 56 patients with advanced solid tumors (phase I); 42 patients with platinum-sensitive, high-grade ovarian carcinoma with germline BRCA1/2 mutation (phase II) Phase I–II clinical trial BRCA1/2-mediated HR, PARP-1/2/3 inhibition 59.5% ORR in phase II, ↓tumor size, manageable toxicity [ 120 ] Rucaparib (600 mg orally, twice daily) 204 patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma (40 BRCA mutant, 82 LOH high, 70 LOH low) Phase II clinical trial BRCA/LOH ↑Progression-free survival in BRCA mutant (12.8 months) and LOH high (5.7 months) vs. LOH low (5.2 months); ↑RECIST responses in BRCA mutant (80%) and LOH high (29%) vs. LOH low (10%) [ 121 ] Rucaparib (dosage not specified) 12 patients with platinum-sensitive, relapsed high-grade epithelial ovarian carcinoma Phase II clinical trial HR, BRCA1/2, RAD51C, RAD51D Secondary mutations in RAD51C and RAD51D restored HR function, conferring resistance to rucaparib [ 122 ] Rucaparib (600 mg orally, twice daily) 349 patients with BRCA1 or BRCA2-mutated ovarian carcinoma, across 64 hospitals in 12 countries Phase III clinical trial BRCA1/BRCA2, RECIST ↑Progression-free survival, ↓Overall survival compared to chemotherapy in ITT population [ 123 ] Rucaparib (600 mg orally, twice daily) 564 patients with recurrent, platinum-sensitive ovarian cancer (375 rucaparib, 189 placebo) Phase III clinical trial BRCA, HRD, ITT ↑PFS, ↑PFS2, no OS benefit, safety consistent [ 124 ] Rucaparib (600 mg orally, twice daily) 425 patients with newly diagnosed advanced ovarian cancer Phase III clinical trial Sustained progression-free survival, manageable safety profile, no new safety signals, low discontinuation rates [ 125 ] Nivolumab (PD-1 inhibitor) Nivolumab: 480 mg intravenously every 4 weeks Rucaparib (600 mg orally twice daily)  ~ 1000 patients with newly diagnosed advanced, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer Phase III clinical trial PD-1 ↑Progression-free survival [ 126 ] Standard-of-Care Chemotherapy (CT) Weekly paclitaxel 60–80 mg/m 2 (platinum-resistant/partially sensitive) or investigator’s choice platinum-based CT (fully platinum-sensitive) Rucaparib (600 mg orally, twice daily) 349 patients (233 rucaparib, 116 CT) with relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, deleterious BRCA1/2 mutation, ≥ 2 prior CT regimens Phase III clinical trial BRCA ↑PFS (rucaparib vs CT in efficacy and ITT populations), no significant difference in ORR, ↓PFS in BRCA reversion mutation subgroup [ 127 ] Rucaparib (600 mg orally, twice per day) 375 patients (ITT), 130 BRCA-mutant, 236 HRD, 107 BRCA wild-type/LOH low Phase III clinical trial ↑PFS, ↑ Quality-adjusted time without symptoms or toxicity [ 128 ] Rucaparib (600 mg orally, twice daily) 564 patients with recurrent high-grade ovarian carcinoma (375 rucaparib arm, 189 placebo arm) Phase III clinical trial BRCA1/2, RAD51C/D, LOH ↑Progression-free survival (PFS ≥ 2 years in 21.1% of rucaparib arm vs 2.1% placebo), especially in BRCA-mutant and HRD patients; ↓Disease progression [ 129 ] Niraparib Doxorubicin Doxorubicin (10:1 molar ratio, encapsulated in folate-conjugated liposomes) Niraparib (9.4 ± 0.6:1 molar ratio with doxorubicin in liposomes) PEO1, PEO4, HEYA8, OVCAR8 cell lines Preclinical, In vitro DNA damage response (dsDNA breaks), FRα-mediated endocytosis ↓Proliferation (synergistic/additive at 10:1 molar ratio in HR-deficient cell lines), Antagonism in HR-proficient PEO4 [ 130 ] Progesterone (P4) 5 mg/kg intramuscularly, 3 times/week in vivo; 10 μM in vitro Niraparib (50 mg/kg by gavage in vivo; 10 μM in vitro) OVCAR3, PEO1, SKOV3, A2780 cell lines, 10 patient-derived organoids (HGSC), Female C57BL/6 and BALB-nude mice, 54 patients with recurrent EOC Preclinical, In vitro and in vivo SCD1-mediated fatty acid oxidation, Ferroptosis ↓Proliferation, ↑Apoptosis, ↑DNA damage, ↑Ferroptosis, ↑Survival (PFS, PFI, OS) [ 131 ] Lactate accumulation Not specified Niraparib (5 µM to > 40 µM in vitro) A2780, HO8910 cell lines, patient-derived organoids, Female nude mice Preclinical, In vitro and in vivo Glycolysis, H4K12la, Nira-SE, RAD23A ↑Niraparib resistance, ↑DNA damage repair [ 132 ] PD-L1 blockade PD-L1 blockade: 10 mg/kg, i.p., twice/week Niraparib (25 mg/kg, oral, 4 times/week) ID8 cells, UWB1.289, SKOV3, C57BL/6 mice, 72 HGSOC patient samples Preclinical, In vitro and in vivo cGAS/STING, PD-L1, CD8 + T cell, CCL5, CXCL10 ↓Tumor growth [ 133 ] GSK3326595 (PRMT5 inhibitor) 50 mg/kg, oral, twice daily Niraparib (35 mg/kg, oral, once daily) OVCAR3, CaOV3, OV-90, other breast/ovarian cell lines, PDX models, NSG and CD.17 SCID female mice Preclinical, In vitro, In vivo DNA damage response, γH2AX, RAD51, 53BP1 ↑DNA damage, ↓Proliferation, Tumor stasis/regression [ 134 ] Oleanolic Acid (OA) Not specified Niraparib (dosage not specified in study) SKOV3, OVCA420 cell lines, tumor tissues and adjacent normal tissues from 20 ovarian cancer patients Preclinical, In vitro and in vivo UNC5B, EMT ↓Proliferation, ↓Invasion, ↓Clonogenesis, ↓EMT, ↑Antitumor activity of niraparib [ 135 ] Anlotinib (multi-target receptor tyrosine kinase inhibitor) 10–12 mg orally, once daily on days 1–14 of each 21-day cycle Niraparib (200 mg or 300 mg orally, once daily, body weight-directed) 40 patients with platinum-resistant recurrent ovarian cancer (PROC) Phase II clinical trial VEGF/VEGFR, PARP ↑Objective response rate (50%), ↑PFS (9.2 months), tolerable toxicity [ 136 ] Dostarlimab (PD-1 inhibitor) 500 mg IV every 3 weeks for Cycles 1–4, 1000 mg IV every 6 weeks thereafter Niraparib (200 mg or 300 mg orally once daily) 41 patients with BRCAwt recurrent platinum-resistant ovarian cancer, previously treated with bevacizumab Phase II clinical trial PD-1 ↓ORR (7.3%), ↓DCR (29.3%), ↓PFS (median 2.1 months), ↓OS (median 10.6 months), ↓HRQoL [ 137 ] Bevacizumab (PD-1 inhibitor) Bevacizumab: 15 mg/kg intravenously, once every 3 weeks; Niraparib: 200 mg or 300 mg orally, once daily (based on body weight and platelet count) Niraparib (200 mg or 300 mg orally, once daily) 105 patients with stage IIIB–IV epithelial ovarian, fallopian tube, or primary peritoneal cancer Phase II clinical trial PD-1 Median OS 61.1 months, no negative impact on HRQOL [ 138 ] Niraparib (200 mg/d or 300 mg/d orally, once daily) 384 patients with newly diagnosed advanced ovarian cancer after first-line platinum-based chemotherapy Phase III clinical trial ↑ PFS, ↓Risk of disease progression or death by 55% [ 139 ] Niraparib (200 mg/day or 300 mg/day, orally, once daily) 265 patients with platinum-sensitive recurrent ovarian cancer (177 niraparib, 88 placebo) across 30 centres in China Phase III clinical trial Favorable OS trend (HR 0.86, 95% CI 0.60–1.23), ↑PFS [ 140 ] Niraparib (200 or 300 mg orally, once daily) 733 patients (487 niraparib, 246 placebo) with newly diagnosed advanced ovarian cancer Phase III clinical trial ↑Gastrointestinal symptoms (nausea, vomiting, appetite loss, constipation); no worsening of overall health-related quality of life (HRQOL) [ 141 ] Niraparib (300 mg once daily) 553 patients with platinum-sensitive recurrent ovarian cancer (PSROC), gBRCAm and non-gBRCAm cohorts Phase III clinical trial ↑PFS, no significant OS difference, no new safety signals [ 142 ] Talazoparib lncRNA HOTAIR Not specified Talazoparib (5 μM, 72 h in vitro) HGSOC cell lines (HRP and HRD) Preclinical, In vitro CHK1, RAD51 ↑PARPi resistance, ↑CHK1 stabilization, ↑Replication fork protection, ↑DNA damage repair [ 143 ] SGI-110 (DNMT inhibitor) 5, 20, or 100 nM in vitro Talazoparib (1 or 10 nM in vitro) A2780, A2780-cp, HeyC2, Kuramochi cell lines Preclinical, In vitro BRCA-mediated DDR ↓Colony formation, ↓Cell survival [ 144 ] ABCC1 and ABCG2 overexpression Talazoparib (0.3 mg/kg oral in vivo; various concentrations in vitro up to 4 μM) A2780, A2780/T4 cell lines, female athymic NCR nude mice Preclinical, In vitro and in vivo ABCC1/ABCG2 efflux ↓Talazoparib sensitivity, ↑Multidrug resistance [ 145 ] Avelumab (PD-1 inhibitor) 10 mg/kg, intravenously, every 2 weeks Talazoparib (1 mg, orally, daily) 35 patients with recurrent mismatch repair proficient endometrial cancer Phase III clinical trial PD-1 ↓Tumor progression, ↑Progression-free survival [ 146 ] Enzalutamide 0.5 mg orally, once daily; Enzalutamide: 160 mg orally, once daily Talazoparib (0.5 mg orally, once daily) 805 men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) Phase III clinical trial PARP, androgen receptor ↓Radiographic PFS (rPFS), ↑Objective response rate, ↑Time to PSA progression, ↑Time to cytotoxic chemotherapy [ 147 ] Veliparib Carboplatin + gemcitabine Carboplatin: AUC 4, i.v., day 1; Gemcitabine: 800 mg/m 2 , i.v., days 1 and 8, 21-day cycle Veliparib (250 mg BID) 75 patients (ovarian cancer, n = 54; breast cancer, n = 12; other cancers, n = 9), 36 with known germline BRCA mutations Phase I clinical trial BRCA1/2, DNA repair ↓Tumor size, ↑PFS (8.6 months in BRCA-mutated ovarian cancer) [ 148 ] Bevacizumab (PD-1 inhibitor) + platinum-based chemotherapy Bevacizumab: 15 mg/kg IV, every 21 days; Carboplatin: AUC 6 IV; Paclitaxel: 175 mg/m 2 IV or 80 mg/m 2 weekly IV or Cisplatin: 75 mg/m 2 IP + Paclitaxel: 135 mg/m 2 IV + 60 mg/m 2 IP Veliparib (150–400 mg BID, continuous or intermittent) 424 patients with stage II-IV epithelial ovarian, peritoneal, or fallopian tube cancer Phase I clinical trial Feasible combination with chemotherapy, no significant impact on PFS/OS [ 149 ] Topotecan 3 mg/m 2 IV, days 2, 9, 16, 28-day cycles Veliparib (30 mg orally, twice daily) 27 patients with advanced epithelial ovarian, fallopian tube, or peritoneal cancer, BRCA1/2 negative or unknown Phase I/II clinical trial DNA repair (PARP, Topoisomerase I) 37% disease control (stable disease), no radiological response, median PFS 2.8 months, median OS 7.1 months [ 150 ] Bevacizumab + durvalumab (PD-1 inhibitor) 15 mg/kg intravenously, once-every-3-weeks + 1.12 g intravenously Olaparib (300 mg orally, twice daily) 74 patients, 41 of whom had platinum-resistant relapse and 33 had platinum-sensitive relapse Phase II clinical trial Feasible combination with chemotherapy, no significant impact on PFS/OS [ 151 ] Veliparib (150 mg orally, twice daily during chemotherapy; 300 mg orally, twice daily for 2 weeks then 400 mg twice daily up to 30 cycles during maintenance) 1140 patients with stage III/IV high-grade serous ovarian cancer Phase III clinical trial ↑PFS, no OS or DRS benefit [ 152 ] Combination strategies involving PARP inhibitors in ovarian cancer: preclinical and clinical outcomes OVCAR3 and TOV112D Female BALB/C-nu/nu mice Preclinical In vitro and in vivo ↓Olaparib sensitivity ↑Proliferation ATRi: 25 mg/kg, oral, 5 days/week, CHK1i: 50 mg/kg, i.p., twice/week ↓DDR ↓EMT Olaparib, a first-in-class PARP inhibitor, has significantly advanced the treatment of ovarian cancer by targeting tumors with homologous recombination deficiency (HRD) and BRCA mutations. Its ability to exploit DNA repair vulnerabilities has positioned it as a key agent in both first-line and recurrent settings [ 153 ]. In newly diagnosed advanced ovarian cancer, the PAOLA-1/ENGOT-ov25 trial demonstrated that maintenance olaparib combined with bevacizumab significantly prolonged progression-free survival (PFS), particularly in HRD-positive patients. Five-year PFS reached 72% in lower-risk HRD-positive patients treated with the combination versus 28% with bevacizumab alone, with a notable improvement in overall survival. These findings highlight olaparib’s potential for durable disease control and long-term remission, even beyond high-risk groups [ 154 ]. In the recurrent setting, studies have confirmed olaparib’s efficacy in platinum-sensitive recurrent ovarian cancer. A retrospective analysis from Kurume University Hospital showed a median PFS of 8.9 months and overall survival of 27.1 months, with HRD identified as a key prognostic factor. Despite manageable side effects, the therapy was well tolerated. Another smaller study found that younger age and lower CA125 levels before treatment predicted prolonged recurrence-free periods, supporting the importance of patient selection. Further supporting these outcomes, the LIGHT study revealed that olaparib benefits patients with both germline and somatic BRCA mutations, with the highest overall survival in BRCA-mutated cohorts. These results underscore the importance of BRCA and HRD testing to guide treatment decisions [ 155 ]. Combination strategies are also showing promise. The MEDIOLA trial reported a 92.2% objective response rate with olaparib plus durvalumab in gBRCAm patients and improved disease control when bevacizumab was added in non-gBRCAm cases, reinforcing the value of olaparib in immunotherapy combinations [ 156 ]. Finally, the timing of disease progression relative to olaparib treatment appears to influence subsequent therapy outcomes. Patients progressing after maintenance therapy had a longer interval before needing further treatment, indicating the durability of olaparib’s effect [ 157 ]. In summary, olaparib plays a central role in the evolving management of ovarian cancer, offering meaningful survival benefits, particularly in biomarker-selected populations. Ongoing studies and real-world data continue to refine its use and expand its potential in combination therapies and personalized treatment strategies. Rucaparib is a potent PARP 1, 2, and 3 inhibitor used in ovarian cancer, especially effective in tumors with HRD, including BRCA1/2 mutations. These molecular vulnerabilities, along with platinum sensitivity, make rucaparib an important option in both treatment and maintenance of high-grade ovarian carcinoma (HGOC) [ 158 ]. Its efficacy was initially established in Study 10, a Phase 1/2 trial of heavily pretreated BRCA-mutated ovarian cancer patients. At a dose of 600 mg twice daily, rucaparib achieved a 59.3% objective response rate (ORR), including in platinum-resistant cases. Most adverse effects were early and manageable; hematologic toxicity occurred later during treatment [ 159 ]. Further support came from the integrated analysis of Study 10 and ARIEL2, which led to European approval of rucaparib monotherapy for relapsed, platinum-sensitive, BRCA-mutated ovarian cancer. Among 79 patients, the ORR was 64.6% with a median response duration of 294 days. Safety data from 565 patients confirmed a tolerable profile, with common adverse events including nausea, fatigue, and anemia [ 160 ]. The Phase 3 ARIEL3 trial evaluated rucaparib as maintenance therapy post-platinum treatment. BRCA-mutated patients saw PFS extended to 16.6 months vs. 5.4 months with placebo. Benefits were also observed in HRD-positive and broader intent-to-treat groups, supporting its use beyond BRCA-mutated populations [ 161 ]. In the ATHENA–MONO trial, rucaparib showed first-line maintenance efficacy in a broader patient cohort. Among advanced HGOC patients responsive to initial platinum-based chemotherapy, median PFS reached 28.7 months in the HRD group and 20.2 months overall, compared to 11.3 and 9.2 months with placebo, respectively [ 162 ]. The ARIEL4 trial compared rucaparib directly with chemotherapy in BRCA-mutated patients after ≥ 2 prior lines of treatment. Rucaparib yielded a median PFS of 7.4 months vs. 5.7 months for chemotherapy, with anemia as the most common adverse event but an overall acceptable safety profile [ 163 ]. Real-world insights from the Spanish Rucaparib Access Program showed that rucaparib could still offer disease control even after prior PARP inhibitor use (mainly olaparib or niraparib) in a heavily pretreated, platinum-resistant population. Despite small sample size, the findings support further study of rucaparib in later-line settings [ 164 ]. To sum up, rucaparib has proven effective across multiple therapeutic contexts, from relapsed treatment to both recurrent and frontline maintenance, even after prior PARP exposure. Its consistent efficacy and manageable toxicity make it a key agent in personalized care for HGOC, particularly in BRCA-mutated and HRD-positive cases. As a potent, selective inhibitor of PARP-1 and PARP-2 with high oral bioavailability, it is up to 100 times more active against these enzymes than other members of the PARP family, underpinning its clinical utility. Approved initially in the EU and USA in 2017 and subsequently in China in 2019, niraparib has transformed treatment paradigms for recurrent ovarian cancer [ 165 ]. The landmark phase III ENGOT-OV16/NOVA trial demonstrated that niraparib significantly prolongs PFS in patients with recurrent ovarian cancer, irrespective of BRCA mutation status. Importantly, patient-reported outcomes indicated that quality of life remained stable during therapy, with no substantial detriment observed from treatment-emergent adverse events such as thrombocytopenia, anemia, and neutropenia. These results reinforced the viability of niraparib as a long-term maintenance option with manageable toxicity [ 166 ]. Supporting its use further, a large phase III Chinese study reaffirmed niraparib’s efficacy in extending PFS in patients with platinum-sensitive recurrent disease. With individualized starting doses (ISD) of 200 mg or 300 mg based on baseline bodyweight and platelet count, the study reported a median PFS of 18.3 months with niraparib compared to 5.4 months with placebo. The safety profile was consistent with global trials, and the ISD approach optimized tolerability without compromising effectiveness [ 167 ]. Beyond maintenance therapy, niraparib also shows promise as an active agent in later lines of treatment. In the QUADRA study, patients who had undergone three or more prior lines of therapy, often with limited alternatives, experienced clinically meaningful responses, especially those with HRD-positive tumors. These outcomes highlight niraparib’s role beyond BRCA-mutated populations, extending its benefit to HRD-positive, BRCA wild-type cases [ 168 ]. Combination strategies are also under investigation. The AVANOVA2 trial demonstrated that pairing niraparib with bevacizumab nearly doubled median PFS compared to niraparib monotherapy. Similarly, first-line maintenance use of niraparib plus bevacizumab showed a high 18-month PFS rate of 62%, particularly benefiting HRD-positive patients [ 169 ]. Finally, a real-world multicenter study in China emphasized the clinical utility of niraparib at 200 mg as an effective and safe dose. The study also identified key predictive factors for extended PFS, including younger age, BRCA mutation status, and optimal cytoreductive surgery, and supported the use of predictive models and nomograms for individualized treatment planning [ 170 ]. Collectively, these findings position niraparib as a versatile and powerful PARP inhibitor in ovarian cancer, effective across a range of clinical scenarios from maintenance therapy to advanced, heavily pretreated disease. Among the arsenal of PARPis under clinical evaluation or approved for treatment, talazoparib and veliparib have emerged with distinctive profiles and promising clinical implications in ovarian cancer therapy. Talazoparib, a potent oral PARP inhibitor, exerts its antitumor effects through a dual mechanism—enzymatic inhibition and PARP-DNA trapping. Its efficacy was first demonstrated in a two-part, phase I, first-in-human clinical trial, which showed single-agent activity in patients with BRCA1/2-mutated cancers, including ovarian carcinoma. At the recommended dose of 1.0 mg/day, talazoparib achieved a 42% confirmed response rate in ovarian cancer patients, accompanied by sustained PARP inhibition at doses ≥ 0.60 mg/day. The safety profile was acceptable, with the most common grade 3–4 toxicities being anemia (24%) and thrombocytopenia (18%), underscoring its manageable toxicity and promising therapeutic index [ 171 ]. Expanding its clinical footprint, talazoparib is being evaluated in combination regimens for first-line treatment. The ongoing JAVELIN Ovarian PARP 100 trial is a landmark phase 3 study investigating talazoparib as part of maintenance therapy in conjunction with avelumab, a PD-L1 inhibitor, following platinum-based chemotherapy. This study targets patients with newly diagnosed stage III–IV epithelial ovarian, fallopian tube, or primary peritoneal cancers. Patients randomized to the talazoparib arm receive 0.75 mg once daily for up to 24 months, with PFS as the primary endpoint. This combination approach aims to enhance immunogenicity and durability of response by leveraging the synergy between DNA damage repair inhibition and immune checkpoint blockade [ 172 – 174 ]. Parallel to talazoparib, veliparib has shown substantial promise in the treatment of high-grade serous ovarian carcinoma. Its role has been extensively studied in the phase 3 VELIA/GOG-3005 trial, which evaluated veliparib when administered concurrently with carboplatin and paclitaxel and continued as maintenance monotherapy. In patients with BRCA mutations, veliparib-throughout treatment significantly extended median PFS to 34.7 months compared to 22.0 months with standard chemotherapy. Similar improvements were seen in the HRD cohort (31.9 vs. 20.5 months) and the broader intention-to-treat population (23.5 vs. 17.3 months). These findings highlight veliparib’s added value when used throughout treatment, particularly in molecularly defined subgroups [ 175 ]. Moreover, veliparib's activity is not restricted to BRCA-mutant cancers. A phase I study assessing veliparib as a single agent demonstrated clinical benefit not only in BRCA-mutated ovarian cancers but also in subsets of BRCA wild-type patients. At doses ≥ 400 mg BID, the objective response rate reached 37% in BRCA-mutant patients, and the treatment was overall well-tolerated. These findings suggest a broader therapeutic window for veliparib, including patients with HRP, as evidenced by numerically improved PFS in the BRCAwt-HRP subgroup in VELIA trial exploratory analyses [ 176 ]. Subgroup analyses from the VELIA trial also revealed that veliparib's benefit extended across different paclitaxel dosing schedules (dose-dense vs. every-3-week) and geographic populations, including Japanese patients, where veliparib-throughout treatment showed numerically longer PFS compared to control arms. Importantly, CA-125 response rates and complete response rates favored veliparib, further supporting its potential utility regardless of biomarker status [ 177 ]. In summary, both talazoparib and veliparib represent pivotal additions to the ovarian cancer treatment paradigm. Talazoparib’s potent PARP-DNA trapping disrupts replication, causing fork collapse and enhanced cytotoxicity in BRCA-mutated cells, achieving a 42% response rate. Conversely, veliparib’s lower trapping efficiency, 100-fold less than olaparib, niraparib, and rucaparib, reduces cytotoxicity but improves tolerability. The VELIA trial showed veliparib’s efficacy across BRCA-mutated and wild-type cohorts. These differences in trapping efficiency guide inhibitor selection based on patient profiles. Talazoparib’s synergy with immunotherapy and veliparib’s broad applicability highlight their roles in precision oncology, advancing tailored therapies for ovarian cancer [ 178 ]. Talazoparib stands out for its potent PARP trapping ability and emerging role in immunotherapy-based regimens, while veliparib has demonstrated broad clinical utility across molecular subtypes and treatment phases. Together, these agents exemplify the evolving landscape of precision oncology in ovarian cancer, laying the foundation for enhanced efficacy through strategic combination and maintenance therapies.

While combining PARP inhibitors with PI3K/AKT/mTOR pathway inhibitors has shown promise in overcoming resistance to PARP monotherapy, emerging evidence indicates that resistance can develop to these combinations themselves. This adaptive resistance may arise from pathway crosstalk, compensatory signaling, genetic/epigenetic alterations, or tumor microenvironment changes, limiting long-term efficacy in ovarian cancer [ 279 ]. Understanding these mechanisms is crucial for optimizing therapeutic strategies and guiding future trial designs. Preclinical studies have identified several key resistance pathways. For instance, in ovarian cancer cell lines treated with olaparib and BKM120 (a PI3K inhibitor), resistance has been linked to upregulation of alternative survival pathways, such as MAPK/ERK signaling, which compensates for PI3K/AKT/mTOR blockade [ 217 , 218 ]. Similarly, in models combining olaparib with alpelisib, persistent activation of mTORC1/2 via feedback loops or autophagy induction has been observed, promoting cell survival despite initial synthetic lethality [ 258 ]. Deng et al. [ 207 ] reported that PARP inhibitor-induced prosurvival signaling changes, including enhanced AKT phosphorylation, could be exacerbated in combination settings, leading to incomplete pathway inhibition. Genetic alterations, such as secondary mutations in PTEN or PIK3CA, further contribute to resistance by restoring downstream signaling [ 220 ]. Additionally, epigenetic modifications, like histone deacetylation or DNA methylation, may reprogram cells to evade dual inhibition, as seen in BRCA-proficient models where autophagy-mediated drug resistance emerges [ 258 , 280 , 281 ]. Clinical insights from trials reinforce these findings. In the phase Ib trial of olaparib plus alpelisib (EPIK-O/ENGOT-OV61), while initial responses were encouraging in PIK3CA-mutated ovarian cancer, disease progression occurred in a subset of patients due to acquired resistance, potentially driven by tumor heterogeneity or microenvironmental factors like hypoxia-induced HIF-1α activation [ 263 ]. Similarly, in trials combining olaparib with capivasertib, resistance has been associated with compensatory activation of RAS/MAPK pathways, highlighting the need for multi-omics profiling to predict non-responders [ 265 ]. Long-term data from maintenance trials, such as PAOLA-1 (olaparib + bevacizumab, with indirect PI3K implications via angiogenesis), suggest that resistance to combinations may involve immune evasion or stromal remodeling, further complicating efficacy in HR-proficient tumors [ 223 ]. To mitigate resistance, biomarker-driven approaches are essential. Molecular stratification using PIK3CA/PTEN status, HRD scores, or phospho-AKT levels can identify patients at risk [ 67 , 220 ]. Novel strategies, including nanotechnology-based delivery systems [ 29 ], may enhance drug penetration and reduce off-target resistance. Additionally, triplet therapies incorporating MEK/ERK inhibitors or autophagy blockers like as chloroquine, have shown preclinical synergy in overcoming combination resistance [ 205 , 282 ]. Ongoing trials, such as those evaluating sequential dosing or adaptive regimens, aim to delay resistance onset [ 263 ]. In summary, while PARP and PI3K/AKT/mTOR combinations effectively address PARP monotherapy resistance, their own limitations underscore the need for vigilant monitoring and innovative countermeasures. Future research should prioritize mechanistic studies and personalized interventions to sustain therapeutic gains in ovarian cancer.

The integration of PARP inhibitors into the therapeutic arsenal for ovarian cancer has revolutionized the management of patients with HR repair deficiencies, particularly those harboring BRCA1/2 mutations. Nevertheless, the efficacy of PARP inhibition remains suboptimal in HR-proficient or BRCA wild-type tumors, which represent a significant proportion of ovarian cancer cases. The exploration of molecular pathways that modulate DNA damage response and repair mechanisms has uncovered the PI3K/AKT/mTOR signaling cascade as a critical player influencing genomic stability, tumor progression, and therapeutic resistance. This review highlights the compelling evidence that dysregulation of the PI3K/AKT/mTOR pathway, via alterations such as PTEN loss, ARID1A mutation, or PI3K/AKT hyperactivation, can compromise HRR and sensitize tumor cells to PARP inhibition. Preclinical models have demonstrated that both genetic and pharmacologic inhibition of this pathway induces synthetic lethality when combined with PARP inhibitors, offering a promising therapeutic strategy to overcome intrinsic or acquired resistance. Notably, combinatorial approaches have shown synergistic antitumor effects, enhanced DNA damage accumulation, and apoptotic induction in a variety of ovarian cancer models. Clinical trials involving dual PI3K/mTOR inhibitors or AKT inhibitors in combination with PARP inhibitors have begun to translate these preclinical successes into clinical potential, particularly in biomarker-selected populations. Nanotechnology-based delivery systems further enhance this therapeutic strategy by improving drug solubility, targeting efficiency, and systemic bioavailability, while reducing off-target toxicity. Such innovations offer a refined approach to combination therapy, potentially overcoming limitations posed by conventional delivery methods and pharmacokinetic challenges. Despite these advances, several limitations must be acknowledged. First, the complexity of the PI3K/AKT/mTOR signaling network poses challenges in achieving sustained inhibition without significant toxicity, as these kinases also regulate essential functions in normal tissues. Second, resistance mechanisms, such as feedback activation of compensatory pathways or mutations that restore HR repair, can undermine therapeutic efficacy. Third, clinical trials exploring these combinations are still in early stages, with many limited by small sample sizes, heterogeneous patient populations, and a lack of validated predictive biomarkers. Moreover, overlapping toxicities, including hematologic and gastrointestinal adverse effects, may constrain dose intensities and impact patient compliance. To address these challenges, future research must focus on several key areas. First, robust biomarker development is critical to guide patient selection and predict therapeutic response. Molecular profiling to identify mutations in ARID1A, PTEN, PIK3CA, or RAS can inform personalized treatment decisions. Second, next-generation PI3K/AKT/mTOR inhibitors with improved selectivity and safety profiles are needed to minimize systemic toxicity and enhance therapeutic windows. Third, integrating PARP/PI3K-targeted therapy with immunotherapy, anti-angiogenic agents, or other modulators of the tumor microenvironment holds significant promise. Such triplet regimens may not only enhance cytotoxicity but also overcome immune suppression and resistance mechanisms. Fourth, longitudinal monitoring of genomic and proteomic changes during treatment may help anticipate resistance and guide adaptive therapeutic strategies. In conclusion, targeting the PI3K/AKT/mTOR pathway offers a rational and promising strategy to enhance PARP inhibitor efficacy in ovarian cancer, especially in patients without canonical BRCA mutations. By impairing homologous recombination and promoting synthetic lethality, inhibitors of this pathway extend the clinical utility of PARP inhibition to a broader patient population. While substantial progress has been made, the journey toward fully realizing the therapeutic potential of this combination requires continued mechanistic studies, biomarker-driven clinical trials, and innovative drug delivery approaches. Through these efforts, precision medicine in ovarian cancer can advance beyond its current boundaries, offering hope for more durable responses and improved survival outcomes across diverse patient subsets.

The integration of PI3K inhibitors and AKT inhibitors with PARP inhibitors has emerged as a promising therapeutic strategy for ovarian cancer, particularly in cases with PIK3CA mutations or platinum resistance [ 214 ]. Preclinical studies have demonstrated that PI3K inhibitors, such as BKM120, exhibit significant anti-tumor activity, both as single agents and in combination with cytotoxic anti-cancer agents, in in vitro and in vivo models of cancers [ 215 ]. BKM120, a pan-class I PI3K inhibitor, has shown anti-proliferative, pro-apoptotic, and anti-tumor effects across various cell lines and xenograft models, regardless of PI3K pathway activation status. Notably, PI3K inhibition by BKM120 impairs HR repair, a critical component of the DNA damage response pathway, leading to increased double-strand break markers, γ-H2AX, and decreased HR repair protein RAD51 in PIK3CA-mutated ovarian cancer cell lines such as SKOV3, HEYA8, and IGROV1. This HR deficiency enhances the dependency on single-strand DNA repair mechanisms, making cancer cells more susceptible to PARP inhibition with agents like Olaparib, thus establishing a synthetic lethal interaction [ 216 ]. The synergy between PI3K inhibitors and PARP inhibitors is further underscored by their impact on BRCA1/2 expression. Studies have shown that PI3K inhibition with BKM120 leads to concomitant downregulation of BRCA1/2, which exacerbates HR deficiency and sensitizes ovarian cancer cells to PARP inhibition. This effect was observed in both PIK3CA-mutated and wild-type PIK3CA ovarian cancer cell lines, suggesting that PI3K inhibitors can broaden the therapeutic scope of PARP inhibitors beyond BRCA-mutated cancers. For instance, in cell lines like OVCAR5, wild-type BRCA, and OVCAR8 and OVCA433, defective BRCA1/2, PI3K inhibition compromised HR repair, enhancing the efficacy of PARP inhibition. Additionally, ex vivo models using surgically resected ovarian cancer specimens have shown that the combination of BKM120 and Olaparib effectively inhibits tumor growth, retaining the tissue architecture and cellularity of primary tumors, further validating this approach [ 217 ]. The combined inhibition of PI3K with PARP inhibitors also addresses resistance mechanisms, such as phosphorylation of S6RP, which confers resistance to PARP inhibitors in BRCA1-deficient cancers. PI3K inhibition with BKM120 nearly abolishes p-S6RP signals in responsive ovarian cancer cell lines, SKOV3, IGROV1, HEYA8, and in vivo models, correlating with enhanced drug sensitivity. However, in resistant cell lines like EFO27, residual p-S6RP signals may contribute to treatment resistance, highlighting the need for further investigation into additional genetic alterations. Moreover, the differential responses in PTEN-deficient cell lines, such as IGROV1, sensitive due to additional BRCA1/2 and ARID1A mutations, versus EFO27, resistant, underscore the complexity of genetic interactions influencing treatment outcomes [ 218 ]. The role of AKT inhibitors in combination with PARP inhibitors also holds significant promise, particularly for platinum-resistant and PARP inhibitor-resistant EOC. AKT inhibition, targeting a central node of the PI3K/AKT/mTOR pathway, induces HR deficiency, enhancing the anti-tumor effects of PARP inhibitors [ 219 ]. In a phase I clinical trial, the combination of the AKT inhibitor Capivasertib and Olaparib achieved clinical benefit in 11 out of 25 patients with advanced EOC, including those with prior PARP inhibitor resistance [ 220 ]. Preclinical studies using mini-PDX and PDX models derived from platinum-resistant EOC patients further confirmed that AKT inhibition additionally enhances the response to PARP inhibition, with notable effects in cell lines expressing high levels of PARP1, such as OVCA433, OVCAR8, and A2780. Intriguingly, AKT inhibition was found to reduce PARP1 protein levels and activity, suggesting an additional mechanism by which AKT inhibitors potentiate PARP inhibitor efficacy beyond HR repair modulation [ 219 ]. Collectively, these findings suggest that combining PI3K or AKT inhibitors with PARP inhibitors represents a robust therapeutic strategy for ovarian cancer, particularly for patients with PIK3CA mutations, BRCA deficiencies, or platinum/PARP inhibitor resistance. The downregulation of BRCA1/2 and PARP1 expression, coupled with impaired HR repair, serves as potential biomarkers for predicting treatment response. While the limited sample sizes in some studies warrant further validation, the consistent preclinical and early clinical evidence supports the continued exploration of these combinations to improve outcomes in ovarian cancer patients with diverse genetic profiles. Kinase inhibitors have emerged as a promising class of targeted therapies in the treatment of ovarian cancer, particularly in overcoming resistance to PARP inhibitors [ 221 ]. These inhibitors target key signaling pathways, such as the PI3K/AKT/mTOR axis, which is frequently dysregulated in ovarian cancer and contributes to cell survival, proliferation, and resistance to chemotherapy [ 46 ]. By combining kinase inhibitors with PARP inhibitors, researchers have demonstrated enhanced tumor cell killing through synergistic effects on the PI3K/AKT/mTOR pathway, offering a novel strategy to improve therapeutic outcomes in cisplatin-resistant and multidrug-resistant ovarian cancer cells. The combination of neratinib, an irreversible inhibitor of ERBB1/2/4, with the PARP inhibitor niraparib has shown additive to synergistic effects in killing ovarian cancer cells in vitro [ 222 ]. Neratinib’s ability to downregulate ERBB1/2/3/4, c-MET, PDGFRα, and mutant K-/N-RAS proteins directly impacts the PI3K/AKT/mTOR pathway, reducing the activities of mTORC1 and mTORC2. This reduction is associated with increased autophagosome and autolysosome levels, driving a toxic form of autophagy that leads to necrotic and necroptotic tumor cell death. The combination also activates ATM-AMPK signaling, which further inactivates AKT, ERK1/2, and NFκB, while enhancing eIF2α phosphorylation. This, in turn, upregulates ATG5 and Beclin1 expression and downregulates anti-apoptotic proteins MCL-1 and BCL-XL, amplifying mitochondrial dysfunction and caspase activation. Notably, neratinib’s unique ability to reduce ERK1/2 phosphorylation, unlike niraparib, enhances BIM expression while decreasing c-FLIP-s, a caspase 8 inhibitor, further promoting apoptosis. This intricate interplay underscores the pivotal role of kinase inhibitors like neratinib in modulating the PI3K/AKT/mTOR axis to enhance PARP inhibitor efficacy [ 223 ]. Similarly, the combination of niraparib with anlotinib, a multi-targeted tyrosine kinase inhibitor, has demonstrated significant anti-tumor activity in ovarian cancer by targeting the PI3K/AKT/mTOR pathway [ 224 ]. Anlotinib’s inhibition of receptor tyrosine kinases reduces PI3K/AKT signaling, leading to decreased phosphorylation of PI3K and AKT, which inhibits EMT and CSC markers [ 225 ]. This combination promotes apoptosis and suppresses tumor cell proliferation and migration, particularly in platinum-resistant recurrent ovarian cancer. The synergistic effect is attributed to anlotinib’s induction of microenvironmental hypoxia, which sensitizes cancer cells to PARP inhibitors by impairing HRR. The reduction in N-cadherin and increase in E-cadherin expression further indicate inhibition of EMT, a key driver of chemotherapy resistance, while the suppression of CSC sphere-forming ability suggests a potential to overcome drug resistance. These findings highlight the critical role of kinase inhibitors like anlotinib in enhancing PARP inhibitor efficacy through targeted modulation of the PI3K/AKT/mTOR pathway [ 224 ]. Brigatinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, also enhances PARP inhibitor activity in HGSOC by targeting tyrosine kinases FAK and EphA2, which are upstream regulators of the PI3K/AKT and MAPK/ERK pathways. By inhibiting FAK and EphA2, brigatinib additively reduces PI3K/AKT and MAPK/ERK signaling, sensitizing both HR-proficient and HR-deficient HGSOC cell lines to PARP inhibitors. Proteomic and cell-based studies confirm that this combination induces tumor regression more effectively than either agent alone in patient-derived xenograft (PDX) models. The suppression of these survival pathways enhances the DNA damage response, as evidenced by increased γH2AX phosphorylation and ATM activation, which aligns with the mechanisms observed in neratinib and anlotinib combinations. This convergence on DNA damage response pathways suggests that kinase inhibitors targeting the PI3K/AKT/mTOR axis can consistently amplify PARP inhibitor-induced tumor cell killing across different molecular targets [ 226 , 227 ]. The c-MET inhibitor crizotinib further exemplifies the potential of kinase inhibitors to augment PARP inhibitor efficacy in HGSOC. By inhibiting c-MET, crizotinib downregulates AKT and ERK signaling, which are critical components of the PI3K/AKT/mTOR pathway, thereby sensitizing tumor cells to PARP inhibitors like olaparib and niraparib. This combination increases γH2AX foci formation and ATM phosphorylation while reducing RAD51 levels, impairing DNA repair and enhancing apoptosis through caspase-3 and PARP cleavage. The activation of p53 and CHK2, coupled with increased p21 and decreased phosphorylated Rb, induces cell cycle arrest, further contributing to tumor cell death. Importantly, crizotinib’s ability to overcome PARP inhibitor resistance in c-MET-overexpressing cells by preventing PARP phosphorylation highlights the strategic importance of kinase inhibitors in addressing resistance mechanisms within the PI3K/AKT/mTOR signaling network [ 228 , 229 ]. Collectively, these studies demonstrate that kinase inhibitors, including neratinib, anlotinib, brigatinib, and crizotinib, enhance PARP inhibitor efficacy by targeting the PI3K/AKT/mTOR pathway and its downstream effectors. By modulating key signaling nodes, such as AKT, ERK, and mTOR, these inhibitors disrupt tumor cell survival, promote apoptosis, and overcome resistance mechanisms, including EMT and CSC maintenance (Fig.  3 ). The consistent induction of DNA damage responses and inhibition of survival pathways across these combinations underscores their therapeutic potential. However, financial and logistical constraints have limited in vivo validation for some combinations, such as neratinib and niraparib, necessitating further preclinical and clinical studies to facilitate translation into clinical practice. These findings provide a robust foundation for developing novel combination therapies to improve outcomes for patients with ovarian cancer, particularly those with resistant or recurrent disease. Fig. 3 Kinase inhibitors targeting the PI3K/AKT/mTOR pathway enhance the efficacy of PARP inhibitors in ovarian cancer . This schematic illustrates the molecular crosstalk between RTKs and the PI3K/AKT/mTOR signaling axis, highlighting key downstream effectors such as ERK, mTOR, and DNA damage repair mechanisms. Kinase inhibitors, including neratinib, anlotinib, brigatinib, and crizotinib, act at various nodes within this pathway to downregulate pro-survival signals and augment PARP inhibitor–induced cytotoxicity. Neratinib (targeting ERBB1/2/4) and anlotinib (a multi-RTK inhibitor) impair EMT and CSC maintenance by modulating AKT and mTOR activities. Brigatinib inhibits FAK and EphA2, suppressing both PI3K/AKT and MAPK/ERK cascades, while crizotinib targets c-MET to further reduce DNA repair capacity and drive apoptosis. The combinations activate ATM/AMPK signaling, reduce RAD51 and BCL-XL expression, enhance γH2AX and CHK2 signaling, and promote transcriptional upregulation of pro-apoptotic genes. These synergistic interactions collectively lead to impaired DNA repair, apoptosis, cell cycle arrest, and suppression of tumor cell proliferation, migration, and therapy resistance, offering a promising therapeutic approach in PARP inhibitor-resistant ovarian cancer Kinase inhibitors targeting the PI3K/AKT/mTOR pathway enhance the efficacy of PARP inhibitors in ovarian cancer . This schematic illustrates the molecular crosstalk between RTKs and the PI3K/AKT/mTOR signaling axis, highlighting key downstream effectors such as ERK, mTOR, and DNA damage repair mechanisms. Kinase inhibitors, including neratinib, anlotinib, brigatinib, and crizotinib, act at various nodes within this pathway to downregulate pro-survival signals and augment PARP inhibitor–induced cytotoxicity. Neratinib (targeting ERBB1/2/4) and anlotinib (a multi-RTK inhibitor) impair EMT and CSC maintenance by modulating AKT and mTOR activities. Brigatinib inhibits FAK and EphA2, suppressing both PI3K/AKT and MAPK/ERK cascades, while crizotinib targets c-MET to further reduce DNA repair capacity and drive apoptosis. The combinations activate ATM/AMPK signaling, reduce RAD51 and BCL-XL expression, enhance γH2AX and CHK2 signaling, and promote transcriptional upregulation of pro-apoptotic genes. These synergistic interactions collectively lead to impaired DNA repair, apoptosis, cell cycle arrest, and suppression of tumor cell proliferation, migration, and therapy resistance, offering a promising therapeutic approach in PARP inhibitor-resistant ovarian cancer Monoclonal antibodies have emerged as a critical class of targeted therapeutics in the treatment of ovarian cancer. Among these, antiangiogenic monoclonal antibodies, particularly those targeting the vascular endothelial growth factor (VEGF) and its receptors (VEGFR), such as bevacizumab, have shown substantial promise [ 230 ]. These agents not only disrupt tumor angiogenesis, which is essential for tumor growth and metastasis, but also exert direct effects on cancer cell survival and sensitivity to treatment through modulation of key intracellular signaling cascades, including the PI3K/AKT/mTOR pathway [ 231 , 232 ]. Bevacizumab, a monoclonal antibody that neutralizes VEGF-A, and cediranib, a small-molecule VEGFR inhibitor, have demonstrated antitumor activity in epithelial ovarian cancer (EOC). Importantly, recent findings have highlighted that VEGF/VEGFR signaling, beyond its angiogenic function, plays a pivotal role in HR repair activity through activation of the PI3K/AKT/CRY1 axis. This is particularly significant as HR proficiency is a key resistance mechanism to PARP inhibitors [ 233 , 234 ]. A recent study revealed that DNA damage stress, including that induced by PARP inhibitors (e.g., olaparib) or irradiation, upregulates VEGF secretion in cancer cells, which in turn activates the VEGFR2/PI3K/AKT pathway. This activation leads to phosphorylation of AKT at key sites: Thr308 by PDK1 (directly downstream of PI3K) and Ser473 by mTORC2, a component of the broader PI3K/AKT/mTOR pathway, establishing a positive feedback loop that sustains pathway hyperactivation. Phosphorylated AKT then inhibits the dimerization of CLOCK and BMAL1, the upstream transcriptional regulators of CRY1, resulting in elevated CRY1 expression, a circadian regulator that stabilizes and temporally controls the expression of HR-related genes, such as RAD51 and BRCA1/2. This enhances RAD51 foci formation at DNA double-strand breaks (DSBs), promotes strand invasion and homology search, and bolsters overall HR repair proficiency, thereby reducing sensitivity to PARP inhibitors in HRP cells [ 235 ]. By blocking VEGF/VEGFR signaling, monoclonal antibodies like bevacizumab suppress the PI3K/AKT/CRY1 axis, resulting in reduced AKT phosphorylation at Thr308, via PDK1, and Ser473, via mTORC2, decreased CRY1 expression, and impaired homologous recombination (HR) activity [ 236 ]. This was demonstrated in preclinical models using HRP cell lines (e.g., OVISE) and HRD lines (e.g., OVSAHO), where co-treatment with bevacizumab or cediranib significantly lowered olaparib IC50 values, inhibited cell proliferation, and reduced RAD51 foci co-localization with γ-H2AX [ 221 ]. Notably, inhibition of VEGFR2 or downstream PI3K, with LY294002, mirrored these effects, substantiating the mechanistic link between VEGF signaling and HR repair via the PI3K/AKT axis [ 235 , 237 ]. Moreover, bevacizumab-induced suppression of CRY1 was reversed by exogenous CRY1 expression, confirming that the enhanced efficacy of PARP inhibitors is mediated through CRY1 downregulation. In this context, mTORC1, activated by AKT, further contributes to resistance by promoting prosurvival signals through phosphorylation of p70S6K and 4E-BP1, which indirectly support HR machinery. Meanwhile, mTORC2’s role in AKT Ser473 phosphorylation amplifies the feedback loop within the PI3K/AKT/mTOR pathway, highlighting why dual PI3K/mTOR inhibitors (as discussed in Sect. 2.1) may synergize with PARP blockade [ 235 , 238 ]. Clinical data support these findings. Phase II and III trials evaluating the combination of bevacizumab or cediranib with olaparib demonstrated improved PFS compared to PARPi alone, even in patients without germline BRCA mutations. The PAOLA-1 study further confirmed a statistically significant benefit of combining bevacizumab with olaparib in the first-line maintenance setting for HR-deficient ovarian cancer [ 239 , 240 ]. In summary, monoclonal antibodies targeting VEGF/VEGFR signaling not only impair angiogenesis but also potentiate PARP inhibitor efficacy by modulating the PI3K/AKT/mTOR pathway, particularly through downregulation of CRY1-mediated HR repair. This dual mechanism enhances DNA damage accumulation in cancer cells, providing a rational basis for integrating monoclonal antibodies into combination regimens with PARP inhibitors in ovarian cancer therapy. Future studies should continue to explore this axis to refine patient selection and optimize therapeutic outcomes. The PI3K/AKT/mTOR pathway, frequently activated by IL-6, drives tumor growth, invasion, and chemoresistance in ovarian cancer. IL-6, secreted by most ovarian cancer cells, triggers multiple signaling cascades, including PI3K/AKT/mTOR and STAT3, via IL-6 receptor and GP130, promoting oncogenes like c-Myc. IL-6 also increases estrogen secretion, amplifying its own production and fueling tumor progression [ 241 ]. Bazedoxifene, a third-generation selective estrogen receptor modulator (SERM), significantly enhances PARP inhibitors efficacy by regulating the PI3K/AKT/mTOR pathway. FDA-approved for postmenopausal osteoporosis, bazedoxifene inhibits IL-6/GP130 signaling, downregulating p-AKT, c-Myc, and p-ERK, and reduces estrogen receptor alpha expression, disrupting oncogenic feedback loops. Its antitumor activity is established in breast, colon, and other cancers, with a favorable safety profile [ 242 ]. In vitro studies combining bazedoxifene with talazoparib, an FDA-approved PARPI, in BRCA wild-type and BRCA-null ovarian cancer cells showed superior inhibition of cell viability, growth, migration, and colony formation compared to monotherapy. This synergy, marked by increased γ-H2AX expression indicating DNA double-strand breaks, leverages bazedoxifene’s suppression of PI3K/AKT/mTOR to enhance talazoparib’s DNA-damaging effects. The combination also reduces cell stemness and migration, key factors in recurrence and metastasis. FDA-approved PARPIs like olaparib and niraparib are now used in BRCA wild-type ovarian cancer, but other combination strategies, such as AKT inhibitors or carboplatin, face limitations due to lack of approval or side effects. Bazedoxifene’s dual role as an IL-6 and PI3K/AKT/mTOR inhibitor makes it a promising partner for PARPIs, offering a novel targeted therapy for ovarian cancer, regardless of BRCA status. Further clinical studies are needed to validate this approach [ 243 ]. Gonadotropin-releasing hormone (GnRH), a hypothalamic neuropeptide, is crucial for reproductive functions by binding to GnRH receptors (GnRH-R) on pituitary gonadotropic cells, stimulating luteinizing hormone and follicle-stimulating hormone release. In humans, GnRH1 and GnRH2 isoforms and a functional type I GnRH-R are expressed [ 244 ]. Notably, GnRH-R is overexpressed in over 80% of ovarian and endometrial cancers and more than 50% of breast cancers, with minimal expression in adjacent normal tissues, making it a valuable diagnostic and therapeutic target. In cancer cells, GnRH-R activation triggers mitogenic or tyrosine kinase signaling, including the PI3K/AKT/mTOR pathway, unlike the protein kinase C activation in pituitary cells [ 245 ]. EP-100, a GnRH receptor inhibitor developed by Esperance Pharmaceuticals, is a fusion peptide of GnRH ligand and an 18-amino-acid cationic lytic peptide, designed to target GnRH-R-overexpressing cancer cells and inhibit the PI3K/AKT/mTOR pathway, enhancing PARP inhibitor efficacy in ovarian cancer. EP-100 induces rapid tumor cell membrane lysis, causing cell death within minutes. Preclinical studies confirm its anti-tumor effects in ovarian, breast, and prostate cancer cell lines, alone or with paclitaxel [ 246 ]. A phase 1 trial demonstrated EP-100’s safety and tolerability across multiple tumors, including ovarian cancer, with no severe toxicity at 0.2 mg/kg, as shown by stable mouse weight and behavior in vivo [ 247 ]. The synergy of EP-100 with olaparib, addresses resistance in ovarian cancer therapy. EP-100 enhances olaparib’s effectiveness by sensitizing BRCA wild-type ovarian cancer cells, likely by inhibiting the PI3K/AKT pathway, a key driver of PARP inhibitor resistance. In vitro and in vivo studies show synergistic effects, even in OVCAR 8 cells with BRCA1 promoter methylation, where BRCA1 protein persists, indicating incomplete gene silencing. As illustrated in Fig.  4 , EP-100’s inhibition of the PI3K/AKT pathway may reduce BRCA1 expression, impairing DNA repair and amplifying olaparib-induced DNA damage. This aligns with findings that PI3K/AKT inhibition enhances PARP inhibitor sensitivity in various cancers. EP-100’s rapid clearance requires prolonged infusion, but its minimal side effects, unlike GnRH agonists causing bone loss or flare phenomena, highlight its therapeutic potential. By targeting GnRH-R and suppressing PI3K/AKT signaling, EP-100 overcomes resistance mechanisms, making it a promising partner for olaparib in BRCA wild-type ovarian cancer [ 248 ]. Future clinical trials should optimize dosing and sequencing to further validate this combination, offering a safer, more effective approach to enhance PARP inhibitor efficacy and improve outcomes in ovarian cancer treatment. Fig. 4 Targeted modulation of the PI3K/AKT/mTOR pathway enhances PARP inhibitor efficacy in ovarian cancer . Combination therapies involving monoclonal antibodies, estrogen receptor modulators, and GnRH receptor-targeted agents synergize with PARP inhibitors by disrupting key oncogenic signaling cascades. Bevacizumab inhibits VEGF-mediated PI3K/AKT/CRY1 signaling, impairing HR repair. Bazedoxifene suppresses IL-6/ERα-driven activation of PI3K/AKT and downstream oncogenes such as c-Myc and p-ERK, enhancing DNA damage in tumor cells. EP-100 targets GnRH-R-expressing cells, blocking PI3K/AKT signaling and sensitizing tumors to PARP inhibition. These combined strategies reduce DNA repair capacity, proliferation, and migration while promoting apoptosis and cell cycle arrest, particularly in HR-proficient and BRCA wild-type ovarian cancers Targeted modulation of the PI3K/AKT/mTOR pathway enhances PARP inhibitor efficacy in ovarian cancer . Combination therapies involving monoclonal antibodies, estrogen receptor modulators, and GnRH receptor-targeted agents synergize with PARP inhibitors by disrupting key oncogenic signaling cascades. Bevacizumab inhibits VEGF-mediated PI3K/AKT/CRY1 signaling, impairing HR repair. Bazedoxifene suppresses IL-6/ERα-driven activation of PI3K/AKT and downstream oncogenes such as c-Myc and p-ERK, enhancing DNA damage in tumor cells. EP-100 targets GnRH-R-expressing cells, blocking PI3K/AKT signaling and sensitizing tumors to PARP inhibition. These combined strategies reduce DNA repair capacity, proliferation, and migration while promoting apoptosis and cell cycle arrest, particularly in HR-proficient and BRCA wild-type ovarian cancers Natural compounds derived from traditional Chinese medicine, including quercetin, curcumin, and icaritin, have emerged as promising adjuncts to enhance the efficacy of PARP inhibitors like olaparib by targeting the PI3K/AKT/mTOR pathway and promoting apoptosis through synergistic mechanisms. These compounds, with their favorable safety profiles and multi-targeted effects, offer a compelling strategy to overcome resistance and improve therapeutic outcomes in BRCA wild-type and cisplatin-resistant ovarian cancer. Quercetin, a bioactive flavonoid found in Astragalus membranaceus (AM), has demonstrated significant potential in inhibiting ovarian cancer cell proliferation and migration while enhancing apoptosis. Network pharmacology and molecular docking studies have revealed that quercetin strongly binds to key oncogenes within the PI3K/AKT/mTOR pathway, including AKT1, as well as other targets such as TP53, MYC, VEGFA, PTEN, and CCND1. These interactions disrupt the signaling cascades that promote tumor growth, thereby inhibiting AKT1 activation and downstream proliferative signals. Experimental validations, including cell scratch, transwell, and cloning assays, have confirmed that quercetin suppresses ovarian cancer cell growth in vitro. When combined with the PARP inhibitor olaparib, quercetin enhances anti-proliferative effects in BRCA wild-type ovarian cancer cells, likely by synergistically impairing DNA repair mechanisms and downregulating AKT-mediated survival pathways. This combination provides a theoretical foundation for further pharmacological exploration, highlighting quercetin’s role in modulating the PI3K/AKT/mTOR axis to augment PARP inhibitor efficacy [ 249 ]. Similarly, curcumin, an active component of Curcuma longa, has garnered attention for its potent inhibition of the AKT/mTOR/p70S6K pathway, which contributes to its anti-tumor effects in ovarian cancer. Curcumin induces apoptosis through the activation of caspases, notably cleaved-Caspase-9 and cleaved-PARP, which serve as executioners of programmed cell death. However, curcumin’s clinical utility is limited by drug resistance mediated by protective autophagy via the AKT/mTOR/p70S6K pathway. Studies have shown that curcumin inhibits phosphorylation of mTOR, p70S6K, and 4E-BP1, disrupting the pathway’s pro-survival signals. To counter autophagy-related resistance, the autophagy inhibitor chloroquine (CQ) has been employed, which blocks curcumin-induced protective autophagy, thereby enhancing curcumin’s cytotoxicity and apoptotic effects in ovarian cancer cell lines such as SK-OV-3 and A2780. The combination of curcumin with CQ significantly increases cell death by suppressing AKT/mTOR-driven autophagy, offering a strategy to overcome resistance and amplify the therapeutic impact of curcumin alongside PARP inhibitors [ 250 ]. Icaritin, a flavonol glycoside derived from Herba Epimedium, further exemplifies the potential of natural compounds in targeting ovarian cancer. Icaritin inhibits the AKT/mTOR signaling pathway while activating p53, a critical tumor suppressor that promotes apoptosis and abrogates AKT/mTOR-driven proliferation. In vitro and in vivo studies, including patient-derived xenograft (PDX) models, have demonstrated that icaritin induces apoptosis in both chemotherapy-sensitive and cisplatin-resistant ovarian cancer cells through suppression of AKT/mTOR signaling and activation of caspase cascades (Caspase-3, Caspase-9, and cleaved-PARP). Notably, icaritin’s anti-tumor effects surpass those of cisplatin in PDX models, with minimal toxicity at doses up to 33 mg/kg, underscoring its safety and efficacy. By downregulating AKT/mTOR activity and enhancing p53-mediated apoptosis, icaritin complements PARP inhibitors, potentially reversing multidrug resistance by modulating pathways such as ABCB1 expression, which is implicated in chemotherapy resistance [ 251 ]. While natural compounds and nanotechnology-based delivery systems offer compelling preclinical evidence for enhancing PARP inhibitor efficacy, their translational limitations must be considered to guide future development. Natural inhibitors such as curcumin and quercetin suffer from poor bioavailability due to low aqueous solubility, rapid hepatic metabolism, and limited gastrointestinal absorption, often resulting in subtherapeutic plasma concentrations in human studies. Clinical trials have also revealed challenges, including inconsistent efficacy across patient cohorts due to variability in compound sourcing, formulation, and dosing, as well as potential toxicity at escalated doses [ 252 , 253 ]. Similarly, nanodelivery systems, while improving drug solubility and targeted delivery, face hurdles in scalability, manufacturing reproducibility, and long-term stability, which can increase production costs and complicate regulatory approval [ 254 – 256 ]. Safety concerns, such as nanoparticle-induced immunogenicity or off-target accumulation in organs like the liver and spleen, have been noted in early-phase trials, potentially limiting their broad adoption [ 257 ]. Nevertheless, these limitations are being actively addressed: bioenhanced formulations (e.g., piperine-coadministered curcumin to inhibit metabolism) and FDA-guided nanoparticle designs (e.g., PEGylated liposomes already approved for doxorubicin in ovarian cancer) have shown improved pharmacokinetics and tolerability in ongoing clinical studies [ 258 ]. The synergistic interplay between quercetin, curcumin, and icaritin with PARP inhibitors lies in their ability to converge on the PI3K/AKT/mTOR pathway and amplify apoptotic signaling. While quercetin enhances olaparib’s efficacy by targeting multiple oncogenes, curcumin overcomes resistance when paired with autophagy inhibitors like CQ, and icaritin provides robust anti-tumor effects across resistant and sensitive cell lines. These natural compounds collectively inhibit key components of the PI3K/AKT/mTOR pathway, including AKT1, mTOR, and downstream effectors like p70S6K, while promoting caspase-mediated apoptosis and p53 activation. Their low toxicity and multi-targeted mechanisms make them ideal candidates for combination therapies with PARP inhibitors, offering a promising approach to address the challenges of drug resistance and tumor heterogeneity in ovarian cancer. Further in vivo studies and clinical trials are warranted to validate these findings and elucidate the precise molecular interactions underlying their synergistic effects. Metformin, a widely used antidiabetic agent, has emerged as a promising adjuvant in ovarian cancer treatment due to its multifaceted influence on the PI3K/AKT/mTOR signaling cascade and DNA repair mechanisms involving PARP [ 259 ]. The hyperactivation of the PI3K/AKT/mTOR pathway is a hallmark of ovarian cancer, contributing to uncontrolled proliferation and resistance to therapy. Targeting this pathway, therefore, offers a compelling strategy to enhance the efficacy of existing therapeutics, including PARP inhibitors [ 16 ]. Experimental evidence supports that metformin exerts anticancer effects both through AKT-dependent and AKT-independent inhibition of mTOR. While classical mTOR inhibitors like rapamycin are limited by feedback upregulation of AKT, metformin circumvents this limitation by activating AMPK, a negative regulator of mTOR [ 260 ]. Furthermore, metformin acts as a partial mitochondrial complex I inhibitor, leading to increased production of reactive oxygen species (ROS), which not only contributes to mitochondrial dysfunction but also triggers apoptosis in ovarian cancer cells. This oxidative stress may function as an upstream signal to modulate the PI3K/AKT pathway, subsequently suppressing mTOR activity. In vitro studies utilizing SKOV-3 ovarian cancer cells have demonstrated that metformin significantly enhances ROS generation, potentiating apoptosis through mitochondrial membrane potential collapse, cytochrome c release, and activation of caspase-3. The drug also increases markers of DNA damage, including H2AX expression, and potentiates the transcription of apoptosis-related genes such as PARP and caspase-3. This cytotoxic cascade is further intensified when metformin is combined with agents like epothilone A or the PI3K inhibitor LY294002, highlighting its potential role in combination therapies [ 261 ]. Importantly, metformin has been shown to elevate the cleaved forms of PARP and caspase-3, aligning with enhanced DNA fragmentation and apoptotic morphology in ovarian cancer models [ 262 ]. Although LY294002 alone induces caspase-3 cleavage, its combination with metformin did not significantly augment this effect. Nevertheless, the parallel inhibition of PI3K and activation of AMPK through this drug pairing led to a synergistic suppression of mTOR activity, thereby exerting a robust antiproliferative effect. The role of metformin becomes even more pronounced when used in combination with PARP inhibitors. PARP enzymes are essential for single-strand break repair, and their inhibition leads to the accumulation of double-strand breaks, ultimately causing cell death in tumors with defective homologous recombination repair. By modulating the PI3K/AKT/mTOR pathway and inducing ROS-mediated DNA damage, metformin may sensitize ovarian cancer cells to PARP inhibitors, enhancing their efficacy even in PARP-resistant settings. Additionally, metformin’s ability to induce cell cycle arrest particularly G1 phase arrest via downregulation of cyclin D1, complements the effects of DNA-damaging agents and PARP inhibitors. It shifts cellular metabolism away from the Warburg effect toward oxidative phosphorylation, thereby acting as a metabolic tumor suppressor. This metabolic reprogramming may further augment the stress on cancer cells subjected to DNA repair inhibition [ 263 ]. Collectively, these findings establish a strong mechanistic rationale for integrating metformin into combination regimens with PARP inhibitors , particularly by targeting the PI3K/AKT/mTOR axis , amplifying ROS production, inducing apoptosis, and impairing DNA repair. This combinatorial strategy holds significant potential in overcoming resistance and improving therapeutic outcomes in ovarian cancer. The development of resistance to PARP inhibitors represents a critical barrier to effective treatment of HGSOC, necessitating innovative strategies to restore therapeutic efficacy. The PI3K/AKT/mTOR signaling pathway has emerged as a pivotal mediator of PARP inhibitor resistance, with its upregulation observed in over 70% of HGSOC cases, contributing to an aggressive tumor phenotype and diminished response to therapy. This pathway’s role in promoting cell survival, inhibiting apoptosis, and facilitating DNA damage repair makes it a prime target for overcoming resistance. Research demonstrates that targeting components of the PI3K/AKT/mTOR pathway can significantly enhance PARP inhibitor efficacy by exacerbating DNA damage, increasing replication stress, and promoting apoptosis in resistant ovarian cancer cells, offering a promising avenue for improving patient outcomes (Fig.  5 ). Fig. 5 Mechanistic overview of the PI3K/AKT/mTOR signaling axis in mediating resistance to PARP inhibitors in ovarian cancer. The diagram illustrates key molecular interactions within the PI3K/AKT/mTOR pathway that contribute to reduced sensitivity to PARP inhibitors. Upstream signals and stress responses, such as ROS, DNA damage markers (γH2AX), and MAPK activation, promote cellular survival mechanisms, including enhanced DNA repair and autophagy. Key inhibitors like as capivasertib, MK-2206, ceralasertib, and natural compound, PS VII, target components of this pathway to disrupt resistance. Inhibiting AKT/mTOR signaling sensitizes cells to PARP inhibitors by increasing DNA damage, impairing repair mechanisms, and inducing apoptosis. Novel therapeutic agents like olaparib-Ga exploit these vulnerabilities, demonstrating potential in overcoming PARPi resistance in both HR-deficient and HR-proficient ovarian cancer cells Mechanistic overview of the PI3K/AKT/mTOR signaling axis in mediating resistance to PARP inhibitors in ovarian cancer. The diagram illustrates key molecular interactions within the PI3K/AKT/mTOR pathway that contribute to reduced sensitivity to PARP inhibitors. Upstream signals and stress responses, such as ROS, DNA damage markers (γH2AX), and MAPK activation, promote cellular survival mechanisms, including enhanced DNA repair and autophagy. Key inhibitors like as capivasertib, MK-2206, ceralasertib, and natural compound, PS VII, target components of this pathway to disrupt resistance. Inhibiting AKT/mTOR signaling sensitizes cells to PARP inhibitors by increasing DNA damage, impairing repair mechanisms, and inducing apoptosis. Novel therapeutic agents like olaparib-Ga exploit these vulnerabilities, demonstrating potential in overcoming PARPi resistance in both HR-deficient and HR-proficient ovarian cancer cells High-throughput drug combination screens have identified synergistic cytotoxicity when combining ATR inhibitors (ATRi), such as ceralasertib, with PI3K/AKT pathway inhibitors, particularly AKT inhibitors (AKTi) like capivasertib, in PARPi-resistant BRCA2-mutant HGSOC cell lines and platinum-resistant lines. These studies revealed that the combination of ATRi and AKTi produced additive or synergistic cytotoxic effects, as validated by XTT and colony formation assays. Notably, this combination significantly increased apoptosis and augmented DNA damage, evidenced by a higher percentage of cells. Furthermore, the treatment enhanced replication stress, with increased phospho-RPA +/γH2AX + populations, underscoring the critical role of PI3K/AKT inhibition in disrupting compensatory survival mechanisms in PARP inhibitor-resistant cells [ 264 ]. The PI3K/AKT/mTOR pathway’s involvement in PARP inhibitor resistance is further highlighted by its interplay with autophagy, a cellular process implicated in adaptive resistance to PARP inhibitos. Studies have shown that olaparib, induces cytoprotective autophagy in ovarian cancer cells, mediated by the inhibition of the AKT/mTOR pathway and upregulation of PTEN expression. This autophagy protects cancer cells from apoptosis, but its inhibition with agents like chloroquine, hydroxychloroquine, or LYS05 enhances olaparib’s cytotoxicity. For instance, combining chloroquine with olaparib in OVCAR8 and patient-derived xenograft models increased cell death by elevating ROS and γH2AX levels, suggesting that disrupting AKT/mTOR-mediated autophagy sensitizes resistant cells to PARPi-induced DNA damage. Additionally, silencing PTEN or inhibiting ATM reduced olaparib-induced autophagy, confirming the pathway’s role in resistance mechanisms [ 265 ]. In BRCA1/2-mutant ovarian cancer, elevated baseline AKT activity compensates for defective HR repair, further driving resistance to PARP inhibitor and platinum-based therapies. The allosteric AKT inhibitor MK-2206 demonstrated synergistic effects with cisplatin and olaparib in BRCA2-mutant PEO1 cells, downregulating AKT phosphorylation at Ser473 and enhancing apoptosis. This synergy arises from targeting AKT’s pro-survival signaling, which overrides apoptotic pathways in the presence of DNA damage, rendering BRCA-mutant cells more susceptible to PARPi. In contrast, BRCA-proficient cells like PEO4 showed less pronounced synergy, likely due to intact HR repair reducing reliance on AKT signaling. These findings highlight that AKT inhibition exploits the synthetic lethality in BRCA-deficient cells, amplifying the therapeutic impact of PARPi [ 266 ]. Gene expression analyses in HGSOC patients have further elucidated the role of the PI3K/AKT/mTOR pathway in PARP inhibitor resistance. In a cohort of 52 patients, pathway enrichment analysis revealed that non-responders exhibited deregulation of PI3K/mTOR signaling, alongside other pathways like PDGFR, FGFR, and MAPK, with key kinases such as JAK1/2 and SRC mediating resistance. Additionally, folate receptor 1 (FOLR1) was significantly upregulated in non-responders, suggesting its potential as a biomarker for PARPi resistance. These molecular insights reinforce the therapeutic potential of targeting the PI3K/AKT/mTOR pathway to counteract resistance mechanisms [ 267 ]. Emerging research also explores natural compounds, such as Paris saponin VII (PS VII), derived from the traditional Chinese herb Paris polyphylla , which targets the PI3K/AKT/mTOR pathway to reverse PARPi resistance. PS VII inhibits glycolysis and angiogenesis, key processes implicated in resistance, by stabilizing RORα, which suppresses the FAK/AKT/GSK3β signaling axis via ECM1/VEGFR2 interactions. This inhibition reduces tumor cell proliferation and enhances apoptosis in PARPi-resistant SKOV3 and HEY cell lines, demonstrating that modulating AKT signaling through natural compounds offers a complementary strategy to overcome resistance. The multi-target nature of PS VII highlights its potential to address the complex regulatory networks driving PARPi resistance [ 268 ]. Innovative nanodrug approaches, such as olaparib-Ga, further underscore the importance of targeting the PI3K/AKT/mTOR pathway. This nanodrug, formed through self-assembly of olaparib with bovine serum albumin and gallic acid gallium(III), suppresses RRM2 expression and inhibits PI3K/AKT signaling while activating Fe2 +/ROS/MAPK and HMOX1 pathways. In HRR-proficient SKOV3 and OVCAR3 cells, olaparib-Ga enhanced DNA damage, increased cleaved-caspase 3 and BAX expression, and reduced tumor growth with minimal toxicity in vivo. These findings indicate that nanodrug-mediated inhibition of PI3K/AKT signaling can sensitize HRR-proficient cells to PARP inhibitors, broadening its therapeutic applicability [ 269 ]. To sum up, the PI3K/AKT/mTOR pathway is a central driver of PARPi resistance in ovarian cancer, promoting cell survival through enhanced DNA repair, autophagy, and anti-apoptotic signaling. Targeting this pathway with inhibitors like capivasertib, MK-2206, or natural compounds like PS VII, as well as novel nanodrugs, significantly enhances PARP inhibitors' efficacy by increasing DNA damage, replication stress, and apoptosis in resistant cells. These strategies, supported by comprehensive molecular and clinical data, offer a robust framework for developing combinatorial therapies to overcome PARP inhibitor resistance, ultimately improving outcomes for patients with HGSOC. Preclinical evidence demonstrating synergy between PARP inhibitors and agents targeting the PI3K/AKT/mTOR pathway, particularly in HR-proficient ovarian cancer models, has spurred clinical investigations into their combined efficacy. The combination of PI3K inhibitors or AKT inhibitors with PARP inhibitors has emerged as a promising strategy to enhance therapeutic outcomes in EOC, especially in patients with de novo or acquired HRR proficiency, where single-agent PARP inhibitors often exhibit limited activity [ 270 ]. Several phase I clinical trials have explored the safety, tolerability, and preliminary efficacy of these combinations, focusing on identifying optimal dosing regimens and assessing their potential to overcome resistance to PARP inhibitors in ovarian cancer (Table  5 ). Table 5 PARP Inhibitor combination therapies and their clinical outcomes Drugs Drug types Clinical trial phase PI3K/Akt/mTOR activity Highlights Ref Olaparib and capivasertib PARP inhibitor and AKT inhibitor phase I ↓PI3K/Akt “ Blockade of AKT downregulated pSer9 pGSK3β, while increased pERK and decreased BRCA1 suggested synergy between capivasertib and olaparib, with antitumor activity seen in germline BRCA1/2-mutant and sporadic DDR/PI3K/AKT-aberrant cancers; RP2D were olaparib 300 mg BID plus capivasertib (400mg BID 4d-on/3d-off or 640 mg BID 2d-on/5d-off), yielding dose-proportional pharmacokinetics, pharmacodynamic-confirmed target modulation, and clinical benefit in 44.6% of evaluable patients, including BRCA1/2-wildtype with pathway alterations.” [ 19 ] Olaparib and capivasertib PARP inhibitor and AKT inhibitor phase I ↓PI3K/Akt “Among 38 enrolled patients (18% with BRCA1/2 mutations), DL1 was established as the RP2D after DLTs (diarrhea/vomiting) resolved; common grade 3/4 toxicities were anemia (23.7%) and leukopenia (10.5%), with a 19% PR rate and 22% stable disease, while response correlated with immune activity/DNA damage and resistance linked to RAS-MAPK/epigenetics. The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian cancer.” [ 271 ] Olaparib and vistusertib PARP inhibitor and mTOR inhibitor Phase I ↓mTOR "Olaparib (O) and vistusertib (V) were tested in two schedules: Arm 1 (BID continuous) and Arm 2 (BID 2 days on/5 days off). RP2D for Arm 2 was O 300mg/V 100mg. Among 49 evaluable patients in Arm 2, response rate (RR) for ovarian cancer was 15%, with a clinical benefit rate of 37%. Common adverse events included nausea (84%), anemia (83%), and fatigue (73%). The combination showed durable activity in ovarian cancer." [ 272 ] Rucaparib PARP inhibitor Phase II ↓Akt “Alterations in AKT1/2/3 or cell cycle pathways (e.g., CCNE1 amplification) in BRCAwt HGOC are associated with poorer PFS in platinum-resistant/refractory patients, suggesting modulation of rucaparib response. Genomic scars (e.g., high LOH) predict rucaparib response in platinum-sensitive disease but not in platinum-resistant/refractory cases; BRCA reversion mutations and BRCA1 demethylation linked to resistance.” [ 273 ] PARP Inhibitor combination therapies and their clinical outcomes A pivotal multicenter, open-label, phase 1b trial evaluated the combination of the PARP inhibitor olaparib with the PI3K inhibitor alpelisib in patients with recurrent EOC of high-grade serous histology or any histology with germline BRCA mutations (gBRCAmut), as well as in triple-negative breast cancer patients with gBRCAmut [ 274 ]. This study, employing a classic 3 + 3 dose-escalation design, enrolled 34 patients, with 30 having EOC and 4 having breast cancer. Patients received alpelisib (200–300 mg once daily) and olaparib (100–200 mg twice daily, tablet formulation). The primary endpoint was to determine the maximum tolerated dose and recommended phase 2 dose (RP2D), established at alpelisib 200 mg daily and olaparib 200 mg twice daily. This combination showed no unexpected toxicities, with the most common grade 3–4 adverse events being hyperglycemia (15.6%), nausea (9.4%), and elevated alanine aminotransferase (9.4%). Dose-limiting toxicities (DLTs) included hyperglycemia and fever with decreased neutrophil count. Notably, the olaparib/alpelisib combination achieved a partial response in 35.7% of EOC patients and stable disease in 50%, per Response Evaluation Criteria in Solid Tumors 1.1. In gBRCA wild-type and platinum-resistant EOC patients, the objective response rate (ORR) was 31.3% and 33.3%, respectively, significantly higher than the ~ 5% ORR expected with olaparib monotherapy in this setting. These findings suggest that alpelisib enhances olaparib’s efficacy in HRR-proficient tumors, aligning with preclinical data showing alpelisib’s ability to inhibit HRR and sensitize ovarian cancer models to PARP inhibitors [ 220 ]. Building on this, another phase I trial investigated the combination of olaparib with the PI3K inhibitors BKM120 in patients with recurrent ovarian or breast cancer, including 35 with gBRCAmut. Using a 3 + 3 dose-escalation design, the study established an maximum tolerated dose of BKM120 50 mg daily and olaparib 300 mg twice daily, constrained by DLTs such as grade 3 transaminitis, hyperglycemia, and depression. This combination demonstrated clinical benefit in both gBRCAmut and gBRCAwt patients, with a 29% ORR in ovarian cancer and 28% in breast cancer. However, toxicities, particularly central nervous system (CNS) effects like depression, limited BKM120 dose escalation, potentially reducing its synergistic potential. Unlike the olaparib/alpelisib trial, where CNS toxicities were absent, the BKM120 combination showed no significant drug-drug interactions but suggested cumulative toxicity, necessitating further pharmacokinetic evaluation. The trial’s preclinical support, derived from patient-derived xenograft (PDX) models, confirmed improved responses over olaparib monotherapy in both BRCA-related and unrelated ovarian cancers, yet no predictive biomarkers were identified, highlighting the complexity of response mechanisms [ 275 ]. Further exploring the PI3K/AKT/mTOR pathway, a phase I trial evaluated the combination of olaparib with the AKT inhibitor AZD5363 in women with advanced cancers, including ovarian, endometrial, and triple-negative breast cancer. This study, which used a 4-day-on/3-day-off schedule for AZD5363 (320–400 mg) and olaparib (300 mg twice daily), confirmed an RP2D of AZD5363 320 mg and olaparib 300 mg twice daily after DLTs of diarrhea and vomiting at higher doses. Among 30 evaluable patients, the ORR was 24%, with notable responses in endometrial cancer (50%) and activity in ovarian and breast cancer. Common adverse events included anemia (89%), nausea (76%), and diarrhea (74%), mostly grade 1–2. This combination showed durable tumor activity, particularly in platinum-resistant settings, with molecular correlative studies ongoing to identify response predictors. The trial’s design allowed for robust safety profiling and provided preliminary evidence of AZD5363 enhancing olaparib’s efficacy in HRR-proficient cancers [ 276 ]. A novel intrapatient dose-escalation trial further assessed olaparib combined with AZD5363 in advanced cancers, including ovarian cancer, using two dosing schedules (4/7 and 2/7 arms). The RP2CD was established at AZD5363 640 mg twice daily (2/7 schedule) with olaparib 300 mg twice daily, based on tolerability. This combination yielded confirmed partial responses in BRCAwt platinum-resistant ovarian cancer, 6 months, and BRCA1-mutant ovarian cancer, 5.5 months +, alongside stable disease in other cancers. The trial’s rapid dose-escalation completion and pharmacodynamic evidence of target inhibition, like as reduced pSer9 GSK3β, underscored the feasibility of this combination in overcoming HRR proficiency. The absence of significant pharmacokinetic interactions and the trial’s innovative design minimized patient numbers while optimizing drug exposure, setting a precedent for future studies [ 277 , 278 ]. Altogether, these trials highlight the potential of combining PI3K or AKT inhibitors with PARP inhibitors to enhance efficacy in HRR-proficient ovarian cancers, particularly in platinum-resistant settings where PARP inhibitors alone have limited activity. The olaparib/alpelisib combination stands out for its favorable toxicity profile and higher response rates in gBRCAwt patients, while BKM120 and AZD5363 combinations faced challenges with dose-limiting toxicities. These studies provide a foundation for further investigation, with ongoing efforts to identify biomarkers and optimize trial designs to confirm the clinical synergism observed, particularly in patients with limited therapeutic options.

Ovarian cancer represents a significant global health burden, recognized as the most lethal gynecologic malignancy due to its insidious onset and propensity for late-stage diagnosis. This limits early detection and increases economic costs. Despite a decade of research, cost-effective prevention strategies remain limited. Treatment costs are among the highest, averaging USD 80,000 in the first year and USD 100,000 in the final year [ 1 , 2 ]. In 2022, the disease accounted for 324,398 new cases worldwide, resulting in 206,839 deaths, underscoring its devastating impact. The high mortality rate is largely attributed to frequent intraperitoneal dissemination, known as peritoneal carcinomatosis, and the development of resistance to platinum-based chemotherapies, which are the cornerstone of ovarian cancer treatment [ 3 , 4 ]. Epithelial ovarian cancers are classified into Type I, indolent tumors arising from precursors like endometriosis, and Type II, aggressive tumors with metastatic potential from small primaries. High-grade serous ovarian cancer, a Type II malignancy comprising ~ 75% of cases, frequently harbors p53 and BRCA mutations, driving its aggressive behavior without recognizable precursor lesions [ 5 , 6 ]. Approximately 50% of ovarian cancer cases exhibit homologous recombination deficiency (HRD), often linked to BRCA1/2 mutations, while the remaining cases demonstrate homologous recombination proficiency (HRP), influencing therapeutic strategies and clinical outcomes [ 7 , 8 ]. These molecular distinctions highlight the urgent need for targeted therapies that address the heterogeneity of ovarian cancer and overcome resistance mechanisms to improve patient survival. Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a transformative therapeutic approach, particularly for HRD-positive ovarian cancers. By targeting PARP enzymes, which are critical for single-strand break (SSB) repair and base excision repair (BER), these inhibitors induce synthetic lethality in cells with defective homologous recombination, such as those with BRCA1/2 mutations [ 9 ]. This mechanism leads to the accumulation of double-strand breaks (DSBs) during replication, triggering apoptosis in cancer cells while sparing normal cells with intact repair pathways. FDA-approved PARP inhibitors, including olaparib, rucaparib, and niraparib, have demonstrated significant efficacy in both first-line and maintenance settings for HRD-positive ovarian cancer, extending progression-free survival and offering hope for durable disease control [ 10 ]. However, their limited efficacy in HRP or BRCA wild-type tumors underscores the need for combination strategies to broaden their therapeutic scope and address resistance mechanisms [ 11 ]. The PI3K/AKT/mTOR signaling pathway, a central regulator of cellular processes such as proliferation, survival, and metabolism, is frequently dysregulated in ovarian cancer, contributing to tumor progression and therapeutic resistance [ 12 ]. Genetic alterations, including PIK3CA mutations, PTEN loss, and AKT/mTOR hyperactivation, drive aberrant signaling that promotes oncogenic processes and modulates DNA damage response, impacting PARP inhibitor sensitivity [ 13 , 14 ]. Studies have elucidated the pathway’s role in enhancing cancer cell survival by activating downstream effectors like mTORC1 and mTORC2, which regulate protein synthesis and cell growth. The PI3K/AKT/mTOR pathway regulates DNA repair, chemoresistance, and genomic stability via DNA replication and cell cycle control. Inhibiting PI3K sensitizes ovarian cancer cells to DNA-damaging agents, overcoming resistance. Additionally, PI3K inhibition reduces Aurora kinase B activity, disrupting the spindle assembly checkpoint and increasing lagging chromosomes in prometaphase, causing genomic instability and mitotic catastrophe. This synergizes with PARP inhibitors, enhancing their efficacy and expanding therapeutic potential in ovarian cancer, particularly in resistant tumors [ 15 , 16 ]. Combining PI3K/AKT/mTOR inhibitors with PARP inhibitors offers a promising strategy to enhance antitumor efficacy and address the limitations of PARP inhibitor monotherapy, particularly in HRP tumors [ 17 ]. Recent evidence demonstrates that co-targeting the PI3K/AKT/mTOR axis can synergize with PARP inhibition by impairing DNA repair, promoting apoptosis, and suppressing prosurvival signaling, thus amplifying synthetic lethality [ 18 ]. Clinical trials exploring this combination, such as those evaluating olaparib with PI3K inhibitors like alpelisib or AKT inhibitors like capivasertib, have shown encouraging results, particularly in patients with PIK3CA mutations or PTEN alterations [ 19 ]. Moreover, advanced delivery systems and inhibitors targeting the PI3K/AKT/mTOR pathway have shown potential in enhancing drug bioavailability and specificity, further supporting the rationale for this combinatorial approach. This review synthesizes preclinical and clinical insights to highlight the therapeutic potential of integrating PI3K/AKT/mTOR inhibition with PARP blockade, emphasizing biomarker-driven strategies to optimize outcomes and transform the treatment landscape for ovarian cancer.

Ovarian cancer remains one of the most lethal gynecologic malignancies due to frequent late-stage diagnosis and the development of resistance to standard therapies, including platinum-based chemotherapy. The introduction of PARP inhibitors has revolutionized the treatment landscape, particularly for patients with homologous recombination repair (HRR) deficiencies such as BRCA1/2 mutations [ 179 ]. However, a substantial proportion of patients with BRCA wild-type (BRCAwt) or HR-proficient tumors fail to respond to PARP inhibitors, highlighting the urgent need to explore molecular pathways that could sensitize these tumors to PARP inhibitors and overcome resistance [ 180 ]. Emerging evidence strongly implicates the PI3K/AKT/mTOR signaling pathway as a key regulator of DNA repair mechanisms and a modulator of PARP inhibitor sensitivity. Dysregulation of this pathway—via genetic alterations such as ARID1A or PTEN loss, or oncogenic activation through RAS mutations—has been linked to impaired HRR capacity and enhanced susceptibility to PARP inhibition (Table  4 ). Table 4 Overview of agents modulating PI3K/Akt/mTOR signaling and parp activity in ovarian cancer Upstream regulator Regulator classification PI3K/Akt/mTOR activity Ovarian cancer cell lines or tissue Type of study PARP activity Axis Highlightes Ref Dihydroptychantol 2 (DHA2) Synthesized macrocyclic bisbibenzyl derivatives ↓Akt/mTOR SKOV3, OVCAR3, 3AO, A2780 Female athymic (BALB/c-nu) mice In vitro and in vivo Cleaved PARP (↓PARP activity) XIAP, Akt/mTOR "DHA2 induces ovarian cancer cell death and protective autophagy. DHA2 affects autophagy-related events, including the inhibition of Akt/mTOR and XIAP and the induction of LC3B-II" [ 181 ] Hispidulin A flavone from traditional Chinese medicine ↓mTOR SKOV3 In vitro Cleaved PARP (↓PARP activity AMPK/mTOR/Mcl-1, Caspase-8 “AMPK is activated upon hispidulin treatment, resulting in mTOR inhibition leading to Mcl-1 decrease, activation of caspases 8 and caspase 3 and consequent PARP cleavage.” [ 182 ] Macranthoside B (MB) Triterpene saponin from Lonicera macranthoides ↓mTOR A2780 In vitro Cleaved PARP (↓PARP activity ROS/AMPK/mTOR “MB induces apoptosis and autophagy in A2780 cells via ROS production, activating caspase-3 and caspase-9, cleaving PARP, upregulating AMPK, and inhibiting mTOR. Autophagy precedes and triggers apoptosis, enhancing cell death.” [ 183 ] MAD2L2 Chromatin-binding protein, component of DNA polymerase ζ ↑Akt/mTOR SKOV3, A2780 In vitro ↓PARP activity (renders PARP inhibitors ineffective in BRCA1-deficient tumors) mTOR, ferroptosis “MAD2L2 is overexpressed in OVCA, correlating with reduced survival rates, particularly in Grade IV tumors. It enhances cell proliferation and migration, inhibits ferroptosis, and is associated with increased mTOR signaling activity.” [ 184 ] Costunolide (CTD) Sesquiterpene lactone ↓mTOR A2780, ES2, CAOV3, Female BALB/c nude mice In vitro and in vivo Cleaved PARP (↓PARP activity AMPK/mTOR, STX17–SNAP29–VAMP8 “CTD inhibits autophagic flux by suppressing AMPK/mTOR signaling and impairing autophagosome–lysosome fusion via disruption of the STX17–SNAP29–VAMP8 complex, leading to autophagy arrest and enhanced cisplatin sensitivity in ovarian cancer cells.” [ 185 ] Quercetin (QU) Polyphenol compound ↓mTOR SKOV3, SKOV3/CDDP In vitro Cleaved PARP (↓PARP activity ROS/Trx/TrxR, mTOR/STAT3, Caspase-9,7,3 “QU pre-treatment sensitizes SKOV-3/CDDP cells to cisplatin by inducing ROS production, inhibiting the Trx/TrxR antioxidant system, downregulating mTOR/STAT3 signaling, and activating the mitochondrial apoptotic pathway (cleaved caspases 9, 7, 3, and PARP), leading to increased apoptosis and cell cycle arrest in sub-G1 phase.” [ 186 ] Torin2 Second-generation mTOR inhibitor ↓mTORC1, ↓mTORC2, ↓AKT MDAH2774, OVCAR, OVSAHO, OVISE, Female nude mice (xenografts) In vitro and in vivo Cleaved PARP (↓PARP activity mTORC1, mTORC2, AKT, P70S6, 4E-BP1, Mitochondrial apoptotic pathway "Torin2 inhibits cell viability and induces apoptosis in EOC cells via inactivation of mTORC1, mTORC2, and downstream targets (P70S6, 4E-BP1, AKT). It downregulates antiapoptotic proteins (XIAP, cIAP1, survivin), activates caspases-9 and −3, and cleaves PARP. Torin2 potentiates cisplatin-induced apoptosis in vitro and in vivo, reducing tumor growth in xenografts." [ 187 ] Honokiol Natural biphenolic compound ↓mTOR SKOV3, Caov-3 In vitro Cleaved PARP (↓PARP activity AMPK/mTOR "Honokiol decreases cell viability in SKOV3 and Caov-3 cells, induces apoptosis via activation of caspase-3, −7, −9, and PARP cleavage, and inhibits migration and invasion through AMPK activation. Compound C reverses these effects, indicating AMPK/mTOR pathway dependency." [ 188 ] Glutamine Amino acid nutrient ↑mTOR HEY, SKOV3, IGROV-1 In vitro ↑PARP expression (depletion induces stress, ↓PARP with glutamine presence) mTOR/S6, MAPK, GLS, GDH "Glutamine promotes ovarian cancer cell proliferation by activating mTOR/S6 and MAPK pathways, increases GLS and GDH activity, reduces ROS and ER stress, and supports ATP and lactate production. Depletion induces G1 arrest, apoptosis, and cell stress." [ 189 ] CDDO-Me Synthetic oleanane triterpenoid ↓AKT/↓mTOR OVCAR-3, OVCAR-5, SK-OV-3, MDAH-2774 In vitro Cleaved PARP (↓PARP activity AKT/NF-κB/mTOR "CDDO-Me inhibits ovarian cancer cell growth by inducing apoptosis via increased annexin V binding, cleavage of PARP-1, procaspases-3, −8, and −9, and mitochondrial depolarization. It inhibits prosurvival p-AKT, NF-κB, and p-mTOR signaling. AKT knockdown enhances sensitivity to CDDO-Me." [ 190 ] MHY2245 Synthetic SIRT inhibitor ↓Akt/mTOR SKOV3, OVCAR3, Female athymic (BALB/c-nu) mice In vitro and in vivo Cleaved PARP (↓PARP activity PKM2/mTOR, SIRT1 "MHY2245 exhibits potent cytotoxicity against SKOV3 cells, inhibits SIRT1 enzyme activity, induces G2/M cell cycle arrest, and promotes apoptosis and autophagy via PKM2/mTOR pathway inhibition." [ 191 ] LTX-315 Onco-immunogenic polypeptide ↓Akt/↓mTOR SKOV3, A2780, SKOV3/DDP, A2780/DDP In vitro Cleaved PARP (↓PARP activity Beclin-1/PI3K/mTOR "LTX-315 reverses cisplatin resistance in ovarian cancer cells by inhibiting cell viability, migration, and invasion, promoting apoptosis via increased cleaved caspase 3, cleaved PARP, and Bax, and arresting the cell cycle. It upregulates Beclin-1 and inhibits p-Akt and p-mTOR, with effects partially reversed by autophagy inhibitor 3-MA." [ 192 ] Asiatic acid Triterpenoid compound from Centella asiatica ↓PI3K/Akt/mTOR SKOV3, OVCAR-3 In vitro Cleaved PARP (↓PARP activity PI3K/Akt/mTOR "Asiatic acid reduces cell viability by ~ 50% at 40 μg/mL, inhibits colony formation by 25–30% at 10 μg/mL, induces G0/G1 phase arrest, increases apoptosis 7- to tenfold, and decreases phosphorylation of PI3K, Akt, and mTOR. Overexpression of active Akt partially reverses effects, while Akt knockdown mimics asiatic acid’s growth-suppressive activity." [ 193 ] CB839, PP242 Small molecule GLS1 inhibitor, Dual mTORC1/mTORC2 inhibitor ↓mTOR C13K, SKOV3 In vitro Cleaved PARP (↓PARP activity PI3K/Akt/mTOR, GLS1/STAT3 "CB839 sensitizes ovarian cancer cells to PP242 by inhibiting GLS1, leading to increased PARP cleavage and apoptosis. The combination reduces p-STAT3, overcoming mTOR inhibitor resistance. PP242 inhibits mTOR activity and cell proliferation but has limited cytotoxic effect, with minimal PARP cleavage, indicating resistance in ovarian cancer cells." [ 194 ] Rapamycin mTOR inhibitor ↓mTOR KF, KOC-2S, SHIN-3, SK-OV-3, TU-OS-3, TU-OS-4 In vitro Cleaved PARP (↓PARP activity c-Jun/Caspase-9, Bcl-xL “Rapamycin enhances etoposide-induced apoptosis via upregulation of phosphorylated c-Jun and downregulation of Bcl-xL, prolonging survival in ovarian cancer xenograft models.” [ 195 ] HGF/c-Met Receptor tyrosine kinase and ligand ↓Akt MDAH2774, SKOV3, OVCAR-3, 156 Saudi EOC patient samples, NUDE mice xenografts In vitro and in vivo Cleaved PARP (↓PARP activity via PHA665752) HGF/c-Met/AKT, XIAP, Bcl-XL, Bax/cytochrome c "c-Met overexpression in 27.2% of EOC samples, associated with advanced tumor stage, XIAP, and Bcl-XL expression. PHA665752 inhibits cell viability, induces apoptosis via Bax-mediated cytochrome c release, caspase activation, and synergizes with cisplatin in vitro and in vivo." [ 196 ] Phenethyl isothiocyanate (PEITC) Isothiocyanate from cruciferous vegetables ↓AKT/mTOR SKOV-3, OVCAR-3, TOV-21G, Female athymic nude mice In vitro and in vivo Cleaved PARP (↓PARP activity EGFR/AKT/mTOR, Caspase-3 "PEITC suppresses ovarian tumor growth by inhibiting EGFR and AKT phosphorylation, disrupting mTOR signaling, and inducing apoptosis via caspase-3 and PARP cleavage. AKT overexpression or TGF treatment blocks PEITC-induced apoptosis." [ 197 ] Curcumin Major active component of turmeric ↓Akt Cisplatin-resistant (CR) and cisplatin-sensitive (CS) human ovarian cancer cells In vitro Cleaved PARP (↓PARP activity Akt, p38 MAPK, p53, caspase-3 "Curcumin inhibits proliferation of CR and CS ovarian cancer cells by inducing superoxide generation, G2/M arrest, and apoptosis via caspase-3 activation and PARP cleavage. It inhibits Akt phosphorylation and enhances p38 MAPK and p53 phosphorylation." [ 198 ] HPIP (Hematopoietic PBX Interacting Protein) Scaffold protein, oncoprotein ↑PI3K/AKT OAW42, SKOV3, PA-1, Primary ovarian tumor samples (grades I-III) In vitro and in vivo Cleaved PARP (↑PARP activity in cisplatin-treated SKOV3 cells post-HPIP knockdown) PI3K/AKT/GSK-3β, Snail/E-cadherin "HPIP is overexpressed in high-grade ovarian tumors, promotes migration, invasion, and EMT via PI3K/AKT pathway activation, stabilizes Snail, represses E-cadherin, and confers cisplatin resistance in SKOV3 cells." [ 199 ] Salinomycin Monocarboxylic polyether antibiotic ↓Akt/NF-κB A2780, A2780cis In vitro Cleaved PARP (↓PARP activity Akt/NF-κB, Caspase-3, Bcl-2 "Salinomycin induces apoptosis in cisplatin-resistant A2780cis cells by inhibiting Akt/NF-κB signaling, downregulating Bcl-2, activating caspase-3, and increasing PARP cleavage. It also augments sub-G1 phase and DNA fragmentation, suggesting potential as a chemotherapeutic agent for cisplatin-resistant ovarian cancer." [ 200 ] Leptin Adipokine, growth factor ↑PI3K/Akt OVCAR-3 In vitro ↓Cleaved PARP (↑PARP activity) JAK2, PI3K/Akt, MEK/ERK1/2, Cyclin D1, Mcl-1 "Leptin stimulates ovarian cancer cell growth and inhibits apoptosis by increasing cyclin D1 and Mcl-1 expression via the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways. JAK2, PI3K/Akt, and MEK/ERK1/2 pathways interact to mediate leptin-induced cell proliferation and anti-apoptotic effects." [ 201 ] MK-2206 Allosteric Akt inhibitor ↓Akt/mTOR SKOV3, ES2 In vitro Cleaved PARP (↓PARP activity Akt/mTOR, p53, Bcl-2, ROS, BRCA1 "MK-2206 enhances Taxol and cisplatin cytotoxicity in SKOV3 (Akt-active) and ES2 (Akt-inactive) cells. In SKOV3, it inhibits Akt, 4E-BP1, and p70S6K phosphorylation, suppresses DNA repair via BRCA1 foci disruption. In ES2, it restores p53, increases ROS, and downregulates Bcl-2, promoting apoptosis. Synergistic effects observed with sequential Taxol or cisplatin followed by MK-2206." [ 202 ] Overview of agents modulating PI3K/Akt/mTOR signaling and parp activity in ovarian cancer SKOV3, OVCAR3, 3AO, A2780 Female athymic (BALB/c-nu) mice A2780, ES2, CAOV3, Female BALB/c nude mice SKOV3, OVCAR3, Female athymic (BALB/c-nu) mice A compelling example is the functional loss or mutation of ARID1A, a chromatin remodeling factor and tumor suppressor. ARID1A deficiency promotes phosphorylation of Akt1 at S473 and T308, resulting in hyperactivation of the PI3K/AKT pathway. This activation, in turn, compromises HR-mediated repair of DNA double-strand breaks (DSBs), rendering tumor cells more dependent on alternative, error-prone DNA repair mechanisms. In ARID1A-mutant TOV-21G ovarian cancer cells, this HR deficiency translated into significantly enhanced sensitivity to PARP inhibitors monotherapy, ABT-888 and olaparib, and PARP inhibitors-radiation combinations. Notably, wild-type ARID1A cell lines, CAOV-3, OVCA-429, and SKOV-3, remained resistant to PARP inhibitors unless ARID1A was silenced. Moreover, pharmacological inhibition of the PI3K/AKT pathway using LY294002 or the Akt-selective inhibitor MK-2206 restored HRR efficiency and reversed PARP inhibitors' sensitivity, underscoring the critical role of PI3K/AKT signaling in regulating HRR and PARP inhibitors' response [ 203 ]. These findings align with similar observations regarding PTEN, another tumor suppressor that negatively regulates the PI3K/AKT axis. PTEN-deficient tumor cells also exhibit HRR defects and heightened sensitivity to PARP inhibitors, both in vitro and in vivo. Restoration of HRR upon PI3K/AKT inhibition in PTEN-mutant cells further supports the concept that PI3K/AKT hyperactivation is a key driver of DNA repair impairment and thus a potential therapeutic target in HR-proficient ovarian cancers [ 204 ]. Beyond ARID1A and PTEN, oncogenic RAS mutations, commonly present in several cancers, including ovarian cancer, have been shown to activate the PI3K/AKT cascade. Bioinformatics screening identified that epithelial ovarian cancer cell lines harboring RAS/PI3K pathway mutations are particularly responsive to combinations of PARP inhibitors with NAMPT inhibitors such as FK866. This combination leads to depletion of NAD +, a critical cofactor for PARP activity, along with increased reactive oxygen species (ROS), DNA damage accumulation, and apoptosis, especially in RAS/PI3K mutant backgrounds. Thus, targeting metabolic dependencies in conjunction with PI3K/AKT-driven repair defects represents a novel approach to enhance PARP inhibitors efficacy [ 205 ]. The dual PI3K/mTOR inhibitor DS-7423 offers additional insights into pharmacologic strategies that exploit this pathway. In ovarian clear cell carcinoma (OCCA) models, DS-7423 significantly inhibited tumor growth in vitro and in vivo, independently of PIK3CA mutational status. Its efficacy was associated with induction of TP53-dependent apoptosis and cleavage of PARP, particularly in TP53 wild-type backgrounds. DS-7423 also downregulated phosphorylation of MDM2 and upregulated phosphorylated TP53 (Ser46), promoting transcription of apoptotic genes such as PUMA and p53AIP1. These data indicate that dual inhibition of PI3K and mTOR not only suppresses proliferation but also amplifies DNA damage responses, synergizing with PARP inhibition [ 204 , 206 ]. Importantly, PARP inhibition itself has been shown to activate AKT, which may serve as a survival mechanism in response to DNA damage. Proteomic studies have revealed that PARP1 and AKT physically interact, with PARP1-mediated PARylation stabilizing AKT activity. Rucaparib treatment was found to reduce AKT PARylation, especially in PARPi-sensitive cells, and combinatorial inhibition of AKT and PARP led to synergistic cytotoxicity even in BRCA-proficient models. These findings suggest that AKT activation can underlie primary or acquired resistance to PARP inhibitors, and its suppression may restore therapeutic sensitivity [ 207 ]. Natural compounds such as cinnamaldehyde have also demonstrated capacity to modulate the PI3K/AKT/mTOR pathway. CA treatment downregulated phosphorylated PI3K, AKT, and mTOR levels in A2780 and SKOV3 cells, both in the presence and absence of EGF stimulation. Furthermore, cinnamaldehyde reversed epithelial-mesenchymal transition (EMT), inhibited invasion, and promoted apoptosis, as evidenced by increased expression of cleaved caspase-3 and cleaved PARP. These findings further support the hypothesis that modulating the PI3K/AKT axis indirectly enhances PARP inhibitor-mediated DNA damage and cell death [ 208 ]. In support of these findings, pristimerin, a quinonemethide triterpenoid with documented anticancer properties, has demonstrated potent activity against ovarian carcinoma cells through inhibition of the AKT/NF-κB/mTOR pathway. Pristimerin treatment resulted in significant suppression of cell proliferation and induction of apoptosis, as evidenced by increased annexin V-binding, mitochondrial depolarization, and cleavage of PARP-1 and caspases-3, −8, and −9. Additionally, pristimerin downregulated anti-apoptotic proteins such as Bcl-2, Bcl-xL, survivin, and c-IAP1, further supporting its therapeutic potential via inhibition of prosurvival signaling pathways intimately tied to PARP resistance [ 209 ]. In addition, the combination of arsenic trioxide (ATO) and PARPi was found to suppress AKT signaling, elevate γH2AX levels, and promote DNA damage and apoptosis in HR-proficient ovarian cancer cells. These effects were associated with reduced phosphorylation of AKT and enhanced cleavage of PARP, reinforcing the rationale for co-targeting PI3K/AKT signaling to potentiate PARP inhibitor-induced DNA damage even in HR-proficient settings [ 210 ]. Moreover, the insulin-like growth factor 1 receptor (IGF-1R) pathway, which feeds into AKT signaling, has been shown to influence PARPi efficacy. In vitro studies using the IGF-1R inhibitor BMS-536924 demonstrated dose-dependent reduction of pAKT and pS6, induction of DNA damage, γ-H2AX, and enhanced PARP-1 cleavage in ovarian cancer cell lines. Importantly, BMS-536924 sensitized cells to the PARP inhibitor 3-aminobenzamide, suggesting that IGF-1R inhibition may augment PARP inhibitors efficacy and overcome resistance through suppression of the AKT axis [ 211 ]. Another critical player in this context is RAD21, a component of the cohesin complex involved in DSB repair and chromatid cohesion. Overexpression of RAD21 promoted activation of the AKT/mTOR pathway, enhanced tumor aggressiveness, and reduced PARPi sensitivity by accelerating DSB repair. Treatment with the mTOR inhibitor PP242 attenuated RAD21-driven resistance, highlighting mTOR as a potential node for overcoming RAD21-mediated PARPi insensitivity [ 212 ]. Additionally, clinical and preclinical data support the use of mTOR inhibitors such as vistusertib (AZD2014) to overcome chemotherapy resistance and enhance PARPi effectiveness. In cisplatin-resistant ovarian cancer models, vistusertib reduced p-AKT and p-S6 levels, induced apoptosis via PARP cleavage, and when combined with paclitaxel, resulted in significant tumor volume reduction. These synergistic effects underscore the potential of dual targeting of mTORC1/2 and DNA repair pathways in drug-resistant ovarian cancer [ 213 ]. In conclusion, a growing body of preclinical and clinical evidence highlights the PI3K/AKT/mTOR pathway as a central modulator of homologous recombination repair, tumor cell survival, and PARP inhibitor sensitivity in ovarian cancer. Aberrant activation of this pathway compromises DNA repair fidelity, rendering tumor cells vulnerable to PARPi through synthetic lethality. Pharmacologic or genetic inhibition of PI3K, AKT, or mTOR components re-sensitizes resistant tumors, enhances DNA damage accumulation, and amplifies apoptotic responses. These insights not only expand the therapeutic scope of PARPi beyond BRCA-deficient cancers but also underscore the potential of rational combination therapies targeting the PI3K/AKT/mTOR axis as a strategy to overcome PARPi resistance in ovarian cancer. Further investigation in clinical trials is warranted to validate these findings and optimize therapeutic regimens for patients with limited treatment options.