PARP抑制剂高选择性地杀伤同源重组修复缺陷肿瘤，是新型抗肿瘤药物。首个该类新药olaparib于2014年获批上市，随后rucaparib和niraparib的治疗效果表现惊人，也相继在2016、2017年被FDA批准上市。然而，现有的PARP抑制剂对BRCA缺陷的卵巢癌应答率仅仅30-50%，意味着过半的病人对治疗无效。同时肿瘤病人对PARP抑制剂均可产生耐药性，最快仅仅6个月就发生耐药，但迄今对预防/克服耐药的策略等缺乏系统研究。为此，本课题拟以新一代抗耐药的抑制剂，SOMCL-15-392为分子探针，系统深入地研究克服PARP抑制剂耐药的分子作用机制，研究结果将对如何增强PARP抑制剂的疗效、治疗耐药后肿瘤提供新思路，并对新一代药物的研发具有重要指导价值；同时对深入解析DNA修复机制、发现PARP抑制剂治疗敏感性的新因素和机制产生有力推动作用。

PARP inhibitors are a new class of anticancer drugs that can selectively kill tumors with homologous recombination defects. The first inhibitor olaparib was approved for cancer therapy in December, 2014. Since then, additional inhibitor, rucaparib and niraparib have demonostrated unexpected therapeutic efficacy and approved by US FDA in 2016 and 2017, respectively. .However, the objective response rates (ORR) to PARP inhibitors are only 30%~50%, even for patients with ovarian cancer associated with BRCA mutations. These data imply that approximately over half of such patients will not respond to treatment. Noticeably, drug resistance occurs as soon as 6 months after PARP inhibitors treatment. There have been no systematic studies on or only very limited understandings about the preventive or overcoming strategies of resistance to these inhibitors. Therefore, this project used a new-generation inhibitors, SOMCL-15-392, as a molecular probe, to investigate the mechanisms on overcoming drug resistance to PARP inhibitors, hopes of providing new insight for enhancing therapeutic effectiveness and overcoming drug resistance of PARP inhibitors, and promoting the development of new-generation inhibitors. Additionally, our newly-obtained results could be greatly helpful to deeply dissect DNA repair mechanisms and find the new factors affecting therapeutic sensitivity to PARP inhibitors.