Synthetic Lethality in Cancer: Mechanistic and Therapeutic Insights into PARP Inhibitors, BRCA Mutations, and Homologous Recombination Deficiency (HRD)

Synthetic Lethality in Cancer: Mechanistic and Therapeutic Insights into PARP Inhibitors, BRCA Mutations, and Homologous Recombination Deficiency (HRD) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Synthetic Lethality in Cancer: Mechanistic and Therapeutic Insights into PARP Inhibitors, BRCA Mutations, and Homologous Recombination Deficiency (HRD) Sonu Kumar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8175121/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) represent a paradigm shift in precision oncology, exploiting synthetic lethality to selectively target tumor cells deficient in homologous recombination repair (HRR) pathways, particularly those harboring BRCA1/2 mutations (Lord & Ashworth, 2017). PARP enzymes, primarily PARP1 and PARP2, are central to the repair of single-strand DNA breaks through the base excision repair pathway. Pharmacologic inhibition of PARP leads to persistent DNA damage accumulation, replication fork collapse, and lethal double-strand breaks in HRR-defective cells (Pommier et al., 2016; Ray Chaudhuri & Nussenzweig, 2017).Loss-of-function mutations in BRCA1, BRCA2, or other HRR genes (e.g., ATM, PALB2, RAD51) define a homologous recombination–deficient (HRD) phenotype that confers enhanced susceptibility to PARPi-induced cytotoxicity (Noordermeer & van Attikum, 2019). The clinical efficacy of PARPi—including olaparib, niraparib, rucaparib, and talazoparib—has been validated in multiple phase III trials across ovarian, breast, prostate, and pancreatic cancers, establishing improved progression-free survival in patients with BRCA-mutant or HRD-positive tumors (Moore et al., 2018; de Bono et al., 2020; Golan et al., 2019).Beyond monotherapy, combination regimens integrating PARPi with anti-angiogenic agents (e.g., bevacizumab), immune checkpoint inhibitors, or DNA damage response (DDR) modulators have demonstrated synergistic potential by amplifying DNA damage, modulating tumor immunity, and overcoming resistance mechanisms (Mirza et al., 2016; Zhou et al., 2024). Circulating tumor DNA (ctDNA)–based HRD assays and genomic scar signatures are emerging as minimally invasive biomarkers for monitoring response and detecting resistance evolution (Hoppe et al., 2022).Despite these advances, unresolved questions persist regarding inter-agent comparability, sequencing in overlapping indications, and optimal biomarkers for HRD detection. Resistance mechanisms, including secondary BRCA reversion mutations, replication fork stabilization, and altered PARP trapping, further limit durable efficacy (Lord & Ashworth, 2017; Lin et al., 2023). Future research integrating multi-omic profiling, standardized HRD testing, and adaptive clinical trial designs will be essential to refine patient selection and expand therapeutic benefit beyond BRCA-mutated populations (Zhou et al., 2024; Lin et al., 2023).In conclusion, PARP inhibition embodies a mechanistically grounded and clinically validated strategy for exploiting synthetic lethality in cancer therapy. Continued elucidation of HRD biology, biomarker evolution, and rational drug combinations will underpin next-generation approaches to overcome resistance and enhance long-term outcomes in precision oncology. PARP inhibitors BRCA mutations Homologous recombination deficiency (HRD) Synthetic lethality DNA damage response Precision oncology Cancer therapeutics Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8175121","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":554590684,"identity":"a50e1666-b9a1-413a-afed-c6d38b60c8bd","order_by":0,"name":"Sonu Kumar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYBAC+QYgwdjAYADmfQBiNnYCWgwOIGlhnAHSwkxICwOSFmYeMElIC3vvMcmfO+yMDa4dfvbZ5tc2eT5mBsYPH3Pw+KXnXJo075lkM4Pbacazc/tuG7YxMzBLztyGx5obOWbSjG0HbAxuJxgz5/bcZgRqYWPmJaBF8idYS/pnZsue2/ZEaZHgbTsAdFiOMTPDj9uJBLUYnDljbM3blmwseTunmLG34XZyGzNjM16/yLf3GN782WZn2Hc7fTPDjz+3bee3Nx/88BGfw1AAYxuYbCBWPQj8IUXxKBgFo2AUjBQAAB6eT4rTQQB8AAAAAElFTkSuQmCC","orcid":"","institution":"Indo Soviet Friendship College of Pharmacy","correspondingAuthor":true,"prefix":"","firstName":"Sonu","middleName":"","lastName":"Kumar","suffix":""}],"badges":[],"createdAt":"2025-11-21 15:53:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8175121/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8175121/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97420974,"identity":"177f9d44-423d-4200-b358-e8d409add20b","added_by":"auto","created_at":"2025-12-04 08:29:40","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":57250,"visible":true,"origin":"","legend":"","description":"","filename":"Cancernov12.3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8175121/v1/039260045b52ff09dbcf5612.docx"},{"id":97420975,"identity":"9c67f7a1-a6fb-4480-a9ba-75f565b3b933","added_by":"auto","created_at":"2025-12-04 08:29:40","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5647,"visible":true,"origin":"","legend":"","description":"","filename":"0ff59d76390e4caab5db4c32fe5f7b57.json","url":"https://assets-eu.researchsquare.com/files/rs-8175121/v1/853b3d338d280497167fe19c.json"},{"id":97666519,"identity":"c740fe5f-cb8a-49d2-b571-2801a4334e9c","added_by":"auto","created_at":"2025-12-08 09:21:25","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":88178,"visible":true,"origin":"","legend":"","description":"","filename":"0ff59d76390e4caab5db4c32fe5f7b571enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8175121/v1/8e133c36ffa5d5daa030fed4.xml"},{"id":97420977,"identity":"73c3e542-597e-4dd2-acaf-a6d0ff178acc","added_by":"auto","created_at":"2025-12-04 08:29:40","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":86092,"visible":true,"origin":"","legend":"","description":"","filename":"0ff59d76390e4caab5db4c32fe5f7b571structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8175121/v1/9e84ed7876abe60c56eb6171.xml"},{"id":97420978,"identity":"22e4dc66-6e83-475f-b592-1e7330978a33","added_by":"auto","created_at":"2025-12-04 08:29:40","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":96685,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8175121/v1/894b4c0817fde6fe7bf8b722.html"},{"id":97677257,"identity":"3b2737fe-40d4-4b1a-b28a-a5058604d7e9","added_by":"auto","created_at":"2025-12-08 09:52:42","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":363068,"visible":true,"origin":"","legend":"","description":"","filename":"Cancernov12.3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8175121/v1_covered_c7a4dbfe-348c-43d4-9fb4-7c710b794947.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Synthetic Lethality in Cancer: Mechanistic and Therapeutic Insights into PARP Inhibitors, BRCA Mutations, and Homologous Recombination Deficiency (HRD)","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PARP inhibitors, BRCA mutations, Homologous recombination deficiency (HRD), Synthetic lethality, DNA damage response, Precision oncology, Cancer therapeutics","lastPublishedDoi":"10.21203/rs.3.rs-8175121/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8175121/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePoly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) represent a paradigm shift in precision oncology, exploiting synthetic lethality to selectively target tumor cells deficient in homologous recombination repair (HRR) pathways, particularly those harboring BRCA1/2 mutations (Lord \u0026amp; Ashworth, 2017). PARP enzymes, primarily PARP1 and PARP2, are central to the repair of single-strand DNA breaks through the base excision repair pathway. Pharmacologic inhibition of PARP leads to persistent DNA damage accumulation, replication fork collapse, and lethal double-strand breaks in HRR-defective cells (Pommier et al., 2016; Ray Chaudhuri \u0026amp; Nussenzweig, 2017).Loss-of-function mutations in BRCA1, BRCA2, or other HRR genes (e.g., ATM, PALB2, RAD51) define a homologous recombination\u0026ndash;deficient (HRD) phenotype that confers enhanced susceptibility to PARPi-induced cytotoxicity (Noordermeer \u0026amp; van Attikum, 2019). The clinical efficacy of PARPi\u0026mdash;including olaparib, niraparib, rucaparib, and talazoparib\u0026mdash;has been validated in multiple phase III trials across ovarian, breast, prostate, and pancreatic cancers, establishing improved progression-free survival in patients with BRCA-mutant or HRD-positive tumors (Moore et al., 2018; de Bono et al., 2020; Golan et al., 2019).Beyond monotherapy, combination regimens integrating PARPi with anti-angiogenic agents (e.g., bevacizumab), immune checkpoint inhibitors, or DNA damage response (DDR) modulators have demonstrated synergistic potential by amplifying DNA damage, modulating tumor immunity, and overcoming resistance mechanisms (Mirza et al., 2016; Zhou et al., 2024). Circulating tumor DNA (ctDNA)\u0026ndash;based HRD assays and genomic scar signatures are emerging as minimally invasive biomarkers for monitoring response and detecting resistance evolution (Hoppe et al., 2022).Despite these advances, unresolved questions persist regarding inter-agent comparability, sequencing in overlapping indications, and optimal biomarkers for HRD detection. Resistance mechanisms, including secondary BRCA reversion mutations, replication fork stabilization, and altered PARP trapping, further limit durable efficacy (Lord \u0026amp; Ashworth, 2017; Lin et al., 2023). Future research integrating multi-omic profiling, standardized HRD testing, and adaptive clinical trial designs will be essential to refine patient selection and expand therapeutic benefit beyond BRCA-mutated populations (Zhou et al., 2024; Lin et al., 2023).In conclusion, PARP inhibition embodies a mechanistically grounded and clinically validated strategy for exploiting synthetic lethality in cancer therapy. Continued elucidation of HRD biology, biomarker evolution, and rational drug combinations will underpin next-generation approaches to overcome resistance and enhance long-term outcomes in precision oncology.\u003c/p\u003e","manuscriptTitle":"Synthetic Lethality in Cancer: Mechanistic and Therapeutic Insights into PARP Inhibitors, BRCA Mutations, and Homologous Recombination Deficiency (HRD)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-04 08:29:35","doi":"10.21203/rs.3.rs-8175121/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5daa78bf-b8d7-47b2-a6fa-91e571080100","owner":[],"postedDate":"December 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-04T23:23:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-04 08:29:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8175121","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8175121","identity":"rs-8175121","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}