新一代PARP抑制剂的抗耐药作用及机制研究

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. 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.

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。

超过40%的BRCA缺陷病人对PARP抑制剂的治疗无效或发生耐药。迄今，仅少量化合物被报道具有克服PARP抑制剂耐药性的潜力。本研究发现了新一代抗耐药的PARP抑制剂，SOMCL-15-392，它广谱地抑制大部分PARP家族亚成员（包括PARP1、PARP2和PARP7等），对同源重组修复缺陷及PARP抑制剂获得性耐药的肿瘤细胞表现出低摩尔级别的细胞毒作用。在耐药细胞中，SOMCL-15-392的活性比已上市的奥拉帕尼和他拉唑帕利的活性强200-6000倍；在体内耐药模型中，口服给予SOMCL-15-392显著抑制不同耐药机制的移植瘤的生长。机制研究结果显示，SOMCL-15-392通过抑制DNA同源重组修复功能及诱导DNA复制压力等方式来发挥抗肿瘤和抗耐药作用。氯喹可部分逆转它在DNA损伤、细胞周期阻滞及增殖生长抑制等方面的效应。此外，它通过p38 MAPK-STAT1通路激活I型干扰素通路；该效应可能依赖于PARP7。因此，新一代PARP抑制剂SOMCL-15-392可同时激活DNA损伤通路和抗肿瘤免疫途径来杀伤肿瘤细胞，为治疗第一代PARP抑制剂耐药后的肿瘤提供了新选择。..此外，我们发现并确证了53BP1、SAMHD1、COX2、BIRC3、FoxO1、MCRS1等可作为PARP1抑制剂潜在生物标志物；同时首次揭示了PARP抑制剂和GSK3抑制剂联合于治疗结肠癌的作用与机制，为治疗PARP抑制剂不敏感人群提供了新策略。总之，本研究深入地探索了克服PARP抑制剂耐药的分子机制及可能的治疗方案，为新一代PARP抑制剂的研发提供了重要参考。.