Abstract 4185: A novel USP1 inhibitor enhances PARP inhibitor efficacy in elevated replication stress tumors: Evidence from BRCA-mutant and CCNE1-amplified models

Abstract Synthetic lethality offers a promising strategy for cancers with elevated replication stress, including BRCA-mutant and CCNE1-amplified tumors. USP1, a deubiquitinating enzyme, stabilizes replication forks by regulating ubiquitinated PCNA (Ub-PCNA). Using the AIGEN ChemTailor AI platform, we developed a novel USP1 inhibitor, which exhibited selective anti-proliferative effects in BRCA-mutant cancer cells and enhanced efficacy when combined with PARP inhibitors in vitro. We evaluated the USP1 inhibitor’s in vivo efficacy in BRCA-mutant breast cancer models and CCNE1-amplified ovarian cancer models. In MDA-MB-436 breast cancer xenografts, the combination of the USP1 inhibitor with PARP inhibitor demonstrated significant tumor suppression in both subcutaneous and orthotopic models, with the orthotopic model better reflecting the cross-talk between tumor cells and the tumor microenvironment. In OVCAR3 ovarian cancer orthotopic metastasis models, the USP1 inhibitor enhanced PARP inhibitor’s anti-tumor activity. Elevated Ub-PCNA expression in tumor tissues from MDA-MB-436 models further supports its potential as a pharmacodynamic marker. These findings highlight the USP1 inhibitor’s potential to enhance PARP inhibitor efficacy in BRCA-mutant and CCNE1-amplified cancers, with Ub-PCNA serving as a promising PD marker. IND-enabling studies, including GLP toxicology, are ongoing, with completion expected by late 2025. Citation Format: Ho-Jeong Lee, Hyerim Yoo, Jihye Kim, Sunkyu Kim, Sejeong Park, Sanghoon Lee, Kiwoong Yoo, Jin Kwan Kim, Kwang-Ok Lee, Jaewoo Kang. A novel USP1 inhibitor enhances PARP inhibitor efficacy in elevated replication stress tumors: Evidence from BRCA-mutant and CCNE1-amplified models [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 4185.