Abstract 4438: Role of USP1 in overcoming chemoresistance Independent of BRCA mutation status

Abstract The efficacy of chemotherapeutic agents like Cisplatin is often limited by DNA repair mechanisms, including the PARP and USP1, that regulates DNA damage response proteins. In this study, we explore the effects of USP1 inhibition, both alone and in combination with a PARP inhibitor, on DNA repair and cell survival following Cisplatin treatment. Our experiments were conducted in a variety of cell lines, irrespective of their BRCA mutation status, to understand the broad applicability of this therapeutic strategy. Cells were treated with Cisplatin to induce DNA damage, followed by treatment with VRTX531 a USP1 inhibitor and/or a PARP inhibitor assessed by in vitro cell based assays such as cell viability, γH2AX foci formation, and comet assay. Inhibition of USP1 resulted in impaired repair of Cisplatin-induced DNA damage, leading to increased sensitivity to subsequent PARP inhibition, regardless of BRCA mutation status. The combination treatment synergistically enhanced cell death, as evidenced by a significant reduction in cell proliferation and an increase in DNA damage markers. These findings suggest that targeting USP1 in combination with PARP inhibition may be a promising therapeutic strategy to overcome chemoresistance, providing a potential treatment approach for tumors with or without BRCA mutations. Further investigation into the mechanistic underpinnings of this combination therapy is warranted to optimize its clinical application. Citation Format: Uday Kumar Surampudi, Prashant Kashinath Bhavar, Partha Pratim Sarma, Anuj Ramesh Kshrisagar, Rishi Rahangdale, Appaji Baburao Mandhare. Role of USP1 in overcoming chemoresistance Independent of BRCA mutation 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 4438.