KSQ-4279, a first-in-class USP1 inhibitor shows strong combination activity in BRCA mutant cancers with intrinsic or acquired resistance to PARP inhibitors

Tumors harboring BRCA1/2 mutations and other homologous repair deficiencies (HRD) are sensitive to agents targeting pathways involved in DNA repair, and multiple molecules that target poly (ADP-ribose) polymerase (PARP), including Olaparib, have been approved for the treatment of BRCA mutant cancers. Despite the clinical benefit achieved with these drugs, many patients achieve incomplete disease control and often develop resistance. By employing our proprietary CRISPRomics® technology to screen over 700 cancer cell lines, we identified the deubiquitinating enzyme USP1 as one of the top targets that displays selective anti-tumor activity in ovarian and triple negative breast cancers. Subsequent drug discovery efforts identified KSQ-4279 as a potent and highly selective first-in-class small molecule USP1 inhibitor that is now in clinical development. We previously demonstrated that KSQ-4279 displays monotherapy potential and combination activity in BRCA mutant cancers that are PARP inhibitor (PARPi) treatment naive. To further investigate the therapeutic potential of KSQ-4279 for treating patients who are either intrinsically resistant, or have developed acquired resistance to PARPi, we performed a number of pre-clinical studies in PARPi-resistant models. KSQ-4279 activity was evaluated in multiple PARPi-resistant, BRCA mutant, ovarian orthotopic PDX models generated from patient tumor samples that have relapsed after multiple rounds of chemotherapy and/or PARPi treatment. While these models did not respond to Olaparib as a monotherapy, the combination of KSQ-4279 and Olaparib led to strong and durable anti-tumor efficacy, including the induction of tumor regressions in several models. Additionally, when we tested KSQ-4279 in combination with Olaparib in PARPi-resistant, BRCA mutant, triple-negative breast cancer (TNBC)-derived PDX models, we observed significantly greater and more durable anti-tumor activity, including regressions, with the combination therapy compared to single agents. The combination of KSQ-4279 was well tolerated over the entire treatment period with no need for dosing holidays, even at the maximum tolerated dose of Olaparib, across all in vivo mouse studies. Our data supports the clinical testing of KSQ-4279 in combination with PARP inhibitors in patients harboring BRCA1/2 mutations that have developed intrinsic or acquired resistance to PARP inhibitors. No conflict of interest.