Abstract 1483: Effect of USP1 inhibitor with or without radiotherapy and chemotherapy on cell viability and biomarkers, independent of BRCA or HRD status

Abstract The efficacy of USP1 inhibitors, which target deubiquitinating enzymes critical to DNA damage response pathways, was evaluated in combination with radiotherapy and chemotherapy across different cellular types including BRCA1/2, BRCA null and, homologous proficient BRCA mutations. Here, we investigate the impact of USP1 inhibition, as single agent or in combination with RT or CT, in a panel of three distinct cell lines, UWB1.289, HCT-116 and NCI H-1792 representing diverse gene alterations and tumor types. Our results demonstrate that USP1 inhibition significantly sensitizes BRCA mutant and HRD proficient cell lines to both RT and CT, amplifying DNA damage and enhancing apoptotic responses. Interestingly, the combination of USP1 inhibitors with UV radiation resulted in significant reduction of cell proliferation in HCT-116, known to demonstrate significantly higher HR activity scores compared with the BRCA1/2 deficient cells, suggesting a broader role of USP1 inhibitor beyond HR deficient cell lines. The synergy between USP1 inhibition and radiotherapy was most pronounced in the HRD+ models, underscoring the potential of USP1 inhibitors as a therapeutic strategy in DNA repair deficient cancers. The activity was established using both the cell viability as well by performing immunofluorescence assay using PCNA as a marker. These findings provide novel insights into the role of USP1 in modulating the response to DNA damaging therapies, with implications for personalized treatment strategies in cancers independent of HRD status. Future studies will explore the underlying molecular mechanisms driving the observed therapeutic synergy and validate these results in-vivo. Citation Format: Mrinal Sivastava, Nirjharni Saha, Partha Pratim Sarma, Prashant Kashinath Bhavar, Uday Kumar Surampudi.. Effect of USP1 inhibitor with or without radiotherapy and chemotherapy on cell viability and biomarkers, independent of BRCA or HRD 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 1483.