Abstract 5992: In vitro efficacy of novel USP1 inhibitors as a single agent and in combination with SOC in ovarian, prostate, and breast cancer cells independent of BRCA mutational status

Abstract Background: Ubiquitin-specific protease 1 (USP1) is a key regulator of DNA repair pathways and is implicated in the response to genotoxic stress. Targeting USP1 has emerged as a potential therapeutic strategy for cancer treatment. This study investigates the in vitro efficacy of a series of novel USP1 inhibitor both as a monotherapy and in combination with other treatment agents, in ovarian, prostate, and breast cancer cell lines. Methods: In vitro efficacy of three different series of USP1i in ovarian (OVCAR-3), prostate (DU-145), and breast (SUM149) cancer cell lines were accessed using cell viability and colony formation assays. Combination included co-treatment with standard chemotherapy agents and determining synergy using composite score. Results: Treatment with USP1i alone led to significant reductions in cell viability and colony formation irrespective of BRCA mutation status. Furthermore, in combination with USP1 inhibitors enhanced efficacy was seen, leading to a positive shift in IC50 in cell viability assay and a significant increase in apoptosis compared to either treatment alone. Conclusion: Our results demonstrate the potent in vitro anti-cancer activity of series of USP1 inhibitors, both as single agent and in combination with chemotherapeutic agents in ovarian, prostate, and breast cancer cell lines, irrespective of BRCA mutational status. These findings suggest that USP1 inhibition could provide a promising therapeutic approach for a broad range of cancers, warranting further investigation in preclinical models and clinical trials. Citation Format: Marina Curcic, Mohamed Eltokhy, Sanjay K. Srivastava, Partha Pratim Sarma, Prashant Kashinath Bhavar, Uday Kumar Surampudi. In vitro efficacy of novel USP1 inhibitors as a single agent and in combination with SOC in ovarian, prostate, and breast cancer cells independent of BRCA mutational status [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 5992.