Abstract 1581: KSQ-4279, a first-in-class USP1 inhibitor shows strong combination activity with multiple PARP inhibitors in BRCA mutant cancers

作者：Erica R. Tobin, Pamela Sullivan, Morgan Murray, Hugh Gannon, Anne E. Dodson, Sol Shenker, Frank P. Stegmeier, Andrew A. Wylie, Louise Cadzow · 发表于：Cancer Research · 年份：2023 · DOI：10.1158/1538-7445.am2023-1581 · 被引用次数：2 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、CRISPR and Genetic Engineering

Abstract Tumors harboring BRCA1/2 mutations and other homologous recombination deficiencies are sensitive to agents targeting pathways involved in DNA repair including poly (ADP-ribose) polymerase (PARP) inhibitors, which have been approved for the treatment of BRCA mutant cancers. Despite the clinical benefit with these drugs, many patients achieve incomplete disease control and often develop resistance. By employing our CRISPRomics® technology to screen over 600 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 with homologous recombination deficiencies. 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. In preclinical models, we previously demonstrated that KSQ-4279 shows therapeutic potential in combination with olaparib for treating patients who are either intrinsically resistant, or have developed acquired resistance to PARP inhibitors. We performed studies to investigate the therapeutic potential of combining KSQ-4279 across a variety of PARP inhibitors with different ‘PARP trapping’ potencies. Clonogenic assays demonstrated synergistic effects of KSQ-4279 across multiple PARP inhibitors regardless of their PARP trapping potency. Second generation PARP1 selective inhibitors such as AZD5305 are currently in clinical developm...