Abstract 2898: SS induces BRCA1 reduction and sensitizes breast cancer cells to PARP inhibitor therapy

Abstract Background: PARP inhibitors (PARPi) have demonstrated substantial clinical efficacy in treating BRCA-mutant breast cancers through synthetic lethality, where the inhibition of DNA single-strand break repair in BRCA-mutant cells leads to the accumulation of DNA damage and cell death. However, in the majority of breast cancer patients with BRCA wild-type (BRCAwt) tumors, PARPi therapy has limited effectiveness. Several approaches, such as CRISPR/Cas9-mediated BRCA1 gene editing, have been explored to induce BRCA deficiency in BRCAwt cancers, but these strategies face challenges for clinical application. Our recent work has focused on novel methods to sensitize BRCAwt breast cancer cells to PARPi. Sulindac sulfide (SS), the active metabolite of the FDA-approved NSAID sulindac, has emerged as a potential agent to enhance cancer cell death when combined with DNA-damaging agents, potentially by impairing DNA repair mechanisms. Methods: This study investigates the mechanisms by which SS inhibits DNA repair, potentially through modulating BRCA1 expression. We assessed the effects of SS on BRCA1 protein levels using western blot analysis and examined BRCA1 mRNA levels using RT-PCR. DNA damage and repair were evaluated by γH2AX foci formation, RAD51 recruitment assays, and slot blot assays. To assess the therapeutic potential of combining sulindac sulfide with PARPi, we conducted both in vitro and in vivo studies. Results: Sulindac sulfide treatment resulted in a dose-dependent reduction of BRCA1 protein levels via ubiquitin-proteasomal degradation. This reduction led to impaired homologous recombination repair capacity and increased DNA damage accumulation. In vitro, the combination of sulindac sulfide and olaparib exhibited synergistic cytotoxic effects in BRCA1wt triple-negative breast cancer (TNBC) cells. In vivo, the combination therapy significantly inhibited tumor growth compared to either agent alone. These findings suggest that sulindac sulfide can sensitize BRCA1wt TNBC cells to PARPi therapy by inducing homologous recombination deficiency. Conclusion: This study provides a mechanistic basis for the combination of sulindac sulfide and PARPi as a potential therapeutic strategy for BRCA1wt TNBC. By downregulating BRCA1 and impairing DNA repair, sulindac sulfide induces a synthetic lethality effect, expanding the therapeutic reach of PARPi to BRCAwt cancers. Citation Format: Jiaqi Chen, Bin Yi, Yaguang Xi. SS induces BRCA1 reduction and sensitizes breast cancer cells to PARP inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2898.