Ixazomib Enhances the Antitumor Effect of Olaparib by Inducing Functional HRD in Ovarian Cancer Cells

Ovarian cancer is characterized by high recurrence rates and frequent development of drug resistance, posing significant challenges to long-term disease control. Although mainte-nance therapy with poly(ADP-ribose) polymerase (PARP) inhibitors such as olaparib has shown clinical benefit in patients with homologous recombination deficiency (HRD), ac-quired resistance limits their sustained efficacy. Here, we screened a library of 2,334 Food and Drug Administration-approved compounds for olaparib sensitizing agents in ovarian cancer cells. Seventy compounds exhibited >50% growth inhibition if combined with olaparib in A2780 cells. Based on IC₅₀ and Cmax values, 17 candidates were identified, and six orally available agents were further evaluated. Among these, ixazomib, a proteasome inhibitor, consistently enhanced olaparib sensitivity in multiple ovarian cancer cell lines. Mechanistic studies revealed that the combination of olaparib and ixazomib significantly enhanced apoptosis and suppressed the formation of RAD51 foci, indicating the induction of functional HRD. In a xenograft mouse model, combination therapy significantly re-duced tumor growth compared to monotherapy, without severe toxicity. These findings suggested that ixazomib enhanced the antitumor activity of olaparib by inducing func-tional HRD, offering a promising and clinically translatable strategy for overcoming PARP inhibitor resistance in ovarian cancer.