DNA 修复途径的缺陷在肿瘤进化和治疗耐药性中发挥着关键作用。同时，它们也会产生一些漏洞，使肿瘤依赖于剩余的 DNA 修复过程。这种现象的例证是 PARP 抑制剂在具有同源重组 (HR) 修复缺陷的肿瘤中的临床活性，例如具有 BRCA1 或 BRCA2 失活突变的肿瘤。然而，BRCA 突变肿瘤对 PARP 抑制剂产生耐药性代表了临床需求尚未得到满足。在这项研究中，我们确定去泛素酶泛素特异性肽酶-1 (USP1) 是具有 BRCA 突变或其他形式 HR 缺陷的肿瘤的关键依赖性，并开发了 KSQ-4279，这是第一个进入临床测试的有效、选择性 USP1 抑制剂。 KSQ-4279 与 PARP 抑制剂的组合具有良好的耐受性，并在多种源自患者的 PARP 耐药模型中诱导持久的肿瘤消退。这些发现表明，USP1 抑制剂代表了一种有前景的治疗策略，可以克服 BRCA 突变/HR 缺陷肿瘤患者对 PARP 抑制剂的耐药性，并支持临床试验中的持续测试。意义：KSQ-4279 是一种有效的选择性 USP1 抑制剂，与 PARP 抑制剂联合用药时可诱导 PARP 抑制剂耐药肿瘤消退，解决了 BRCA 突变肿瘤未得到满足的临床需求。©2024由美国癌症研究协会出版。

Defects in DNA repair pathways play a pivotal role in tumor evolution and resistance to therapy. At the same time, they create vulnerabilities that render tumors dependent on the remaining DNA repair processes. This phenomenon is exemplified by the clinical activity of PARP inhibitors in tumors with homologous recombination (HR) repair defects, such as tumors with inactivating mutations in BRCA1 or BRCA2. However, the development of resistance to PARP inhibitors in BRCA-mutant tumors represents a high unmet clinical need. In this study, we identified deubiquitinase ubiquitin-specific peptidase-1 (USP1) as a critical dependency in tumors with BRCA mutations or other forms of HR deficiency and developed KSQ-4279, the first potent and selective USP1 inhibitor to enter clinical testing. The combination of KSQ-4279 with a PARP inhibitor was well tolerated and induced durable tumor regression across several patient-derived PARP-resistant models. These findings indicate that USP1 inhibitors represent a promising therapeutic strategy for overcoming PARP inhibitor resistance in patients with BRCA-mutant/HR-deficient tumors and support continued testing in clinical trials. Significance: KSQ-4279 is a potent and selective inhibitor of USP1 that induces regression of PARP inhibitor-resistant tumors when dosed in combination with PARP inhibitors, addressing an unmet clinical need for BRCA-mutant tumors.©2024 The Authors; Published by the American Association for Cancer Research.