105 (PB095) - KSQ-4279, a first-in-class USP1 inhibitor shows strong combination activity in BRCA mutant cancers with intrinsic or acquired resistance to PARP inhibitors

Abstract

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.