Abstract 4433: Effectiveness of USP1 inhibitor (VRTX531) in gynecological cancers with diverse BRCA mutation status
Authors: Uday Kumar Surampudi, Prashant Kashinath Bhavar, Partha Pratim Sarma, Rishi Rahangdale, Anuj Ramesh Kshirsagar, Appaji Baburao Mandhare
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer and Ovarian cancer are aggressive malignancies often associated with poor prognoses due to their high recurrence rates and limited targeted treatment options. TNBC, which lacks expression of estrogen, progesterone, and HER2 receptors, accounts for 10-15% of breast cancers and disproportionately affects younger women, those with BRCA1 mutations, and certain ethnic groups, such as Black women. Similarly, ovarian cancer is often diagnosed at advanced stages and includes subtypes like high-grade serous carcinoma, which is strongly linked to BRCA1/2 mutations and homologous recombination deficiency. Both cancers share vulnerabilities in DNA damage repair pathways, making them promising candidates for treatments like PARP inhibitors and novel agents targeting DDR mechanisms. However, only 20-40% of the patients benefit from PARPi and are alive 5-years after diagnosis from these gynecological cancers. Ubiquitin specific protease 1 belongs to a group of deubiquitinating enzymes and is a key regulator in the DNA damage repair (DDR) pathway. A deficiency in USP1 results in compromised genomic stability, making it a potential therapeutic target in tumors that exhibit defects in the DNA damage repair mechanism. VRTX531 is a potent, selective, and allosteric oral inhibitor of USP1, specifically designed to target HRD Tumors. Treatment with VRTX531 resulted in decreased viability in cell lines with BRCA1/2 mutations and HRD+ tumors. USP1 inhibitors are anticipated to induce cell death via a pathway distinct from PARPi, and thus have the potential to overcome resistance to PARPi. The synergistic effect of VRTX531 combined with PARPi was demonstrated in cell-based assays representing these gynecological cancers representing BRCA mut, HRD+, MDA-MB-436 and BRCA null, HRD+, UWB1.289. Moreover, VRTX531 exhibited a significant synergistic effect in vitro when used in conjunction with a PARP inhibitor. These results indicate that VRTX531 not only provides substantial monotherapy benefits but also improves the effectiveness of PARP inhibition. The cell viability assay revealed a dose-dependent reduction in cell proliferation, with VRTX531 demonstrating potent anti-proliferative effects which was further confirmed by clonogenic assays. DNA damage was evaluated by γH2AX foci formation which showed a marked increase in DNA damage upon treatment with VRTX531. Our Previous work demonstrated that treatment with PARPi alone led not only to a delayed onset of response but also showed statistically significant variability between subjects, in contrast the combination of VRTX531 and PARPi led to rapid onset of response, followed by complete tumor regression with an TGI &amp;gt;98%, in a TNBC Xenograft of MDA-MB-436. USP1 inhibitor VRTX531, exhibits best-in-class pharmacokinetics, with exemplary safety profile, that supports its further development. Citation Format: Uday Kumar Surampudi, Prashant Kashinath Bhavar, Partha Pratim Sarma, Rishi Rahangdale, Anuj Ramesh Kshirsagar, Appaji Baburao Mandhare. Effectiveness of USP1 inhibitor (VRTX531) in gynecological cancers with diverse 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 4433.