新型高选择性抗肿瘤PARP抑制剂的耐药特性和机制研究

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. We are preparing for IND applications of 2 new PARP inhibitors. All tumors could acquire drug resistance to PARP inhibitors, which becomes one of critical factors limiting their therapeutic effectiveness. However, there have been no systematic studies on or only very limited understandings about the characteristics, mechanisms and preventive or overcoming strategies of resistance to these inhibitors. Noticeably, there may exist large differences in characteristics and mechanisms of drug resistance among PARP inhibitors and homologous recombination defects; moreover, such large differences may appear in different patients with the same type of cancer and with the same PARP inhibitor for therapy. Our preliminary data also showed that there may lack apparently cross resistance between some PARP inhibitors, and that there may exist multiple machanisms remaining to be uncovered. Therefore, this project is designed to relatively systematically investigate the characteristics, mechanisms and preventive or overcoming strategies of drug resistance to PARP inhibitors, in hopes of providing new data for preventing or overcoming drug resistance emergence, enhancing therapeutic effectiveness 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 mechnisms and find the factors affecting therapeutic sensitivity to PARP inhibitors.

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；首个该类新药于2014年获批上市，我们也正在准备申报2种自主研发的抑制剂的临床试验。肿瘤对PARP抑制剂均可产生耐药性，成为阻碍其治疗成功的关键因素之一，但迄今对其耐药特性、机制及预防/克服策略等仍缺乏系统研究和深入了解。特别重要的是，不同抑制剂、不同遗传缺陷肿瘤耐药性产生特点、规律和机制存在很大差异；即使同一抑制剂在同一类肿瘤的不同患者，其耐药特点与产生机制也可能存在很大差异。我们的初步结果显示，部分抑制剂之间可能缺乏明显的交叉耐药性，多种未知的耐药机制也亟需探索。为此，本课题拟系统深入地研究PARP抑制剂的耐药特性、产生机制及预防和克服措施，结果对防止或延缓耐药性产生，充分发挥其抗肿瘤作用、促进新一代药物的研发具有重要指导价值；对于深入解析DNA修复机制、发现影响PARP抑制剂治疗敏感性的因素和机制将产生有力推动作用。

本研究采用药物诱导、遗传学干预方法建立PARP抑制剂c细胞株，阐明了PARP抑制剂临床前耐药的一般规律；发现BRCA2内含子11的新突变体、抗凋亡蛋白COX-2和BIRC3过表达介导的凋亡耐受贡献于PARP抑制剂耐药；发现PARP1负调控COX-2和BIRC3转录、过表达COX-2和BIRC3可能为PARP抑制剂耐药性潜在的预测标志物；揭示PARP1的聚合酶活性与PARP抑制剂细胞毒性高度相关、PARP1的聚合酶活性降低是耐药机制之一；阐明了抑制与DNA结合的PARP1的PAR生成、增加PARP1-DNA复合物是PARP抑制剂细胞毒性的关键机制；阐明了53BP1缺陷/减少是BRCA1及PTEN缺陷细胞对PARP抑制剂耐药机制之一、53BP1水平+BRCA1缺陷可作为PARP抑制剂敏感患者选择的潜在组合标志物；获得了一种具有显著克服PARP抑制剂耐药性的候选新药噻奥哌瑞。本研究结果对PARP抑制剂耐药性提供了新的认识，对建立预防和克服PARP抑制剂耐药性的可能策略、方法与途径提供了有益的线索。