卵巢癌中PARP抑制剂的耐药机制及提高其敏感性的联合治疗策略

doi:10.12280/gjfckx.20230329

摘要/Abstract

摘要：

卵巢癌是致死率最高的妇科恶性肿瘤。多腺苷二磷酸核糖聚合酶抑制剂[poly(ADP-ribose) polymerase inhibitor，PARPi]通过酶促抑制和PARP“捕获”使DNA单链断裂修复受损，从而在具有乳腺癌相关基因（breast cancer-related gene，BRCA）缺陷或同源重组修复缺陷的肿瘤细胞中通过合成致死效应推动其在卵巢癌维持治疗上的应用。但PARPi的耐药性成为PARPi长期应用的障碍。目前研究显示，PARPi获得性耐药的机制包括同源重组修复恢复、DNA复制叉保护、PARP“捕获”减少及药物外排增加等。通过针对特定的耐药机制，目前正在研究的主要的联合治疗策略有PARPi与抗血管生成剂、细胞周期检查点蛋白抑制剂、信号通路抑制剂、免疫治疗和表观遗传修饰剂等联合，可能有助于预防和对抗PARPi的耐药性，从而提高PARPi的敏感性和抗肿瘤作用。

关键词: 多（ADP核糖）聚合酶抑制剂, 卵巢肿瘤, 抗药性, 肿瘤, 药物疗法, 联合

Abstract:

Ovarian cancer is the most lethal gynecological malignancy. Poly (ADP-ribose) polymerase inhibitor (PARPi) impairs the repair of DNA single-stranded breaks through enzymatic inhibition and PARP "trapping". The synthetic lethal effect of PARPi in combination with tumor cells with a breast cancer-related gene (BRCA) deficiency or defective in homologous recombination repair (HRR) in ovarian cancer promoting its application in the maintenance therapy of ovarian cancer. However, resistance to PARPi is an obstacle to the long-term use of PARPi. A number of studies have described mechanisms of acquired resistance to PARPi, which include broadly HRR recovery, replication fork protection, reduced PARP "capture", and increased drug efflux. By targeting specific resistance mechanisms, the main combination therapeutic strategies currently being investigated include combining PARPi with anti-angiogenic agents, cell cycle checkpoint protein inhibitors, signalling pathway inhibitors, immunotherapy, epigenetic modifiers, etc. A combination therapy strategy of drugs has the potential to prevent and counteract PARPi resistance, thereby improving PARPi′s sensitivity and antitumor effects.

Key words: Poly(ADP-ribose) polymerase inhibitors, Ovarian neoplasms, Drug resistance, neoplasm, Drug therapy, combination

李宾, 吝欢欢, 韩飞飞, 田美玲, 段爱红, 柯小宁. 卵巢癌中PARP抑制剂的耐药机制及提高其敏感性的联合治疗策略[J]. 国际妇产科学杂志, 2023, 50(5): 563-567.

LI Bin, LIN Huan-huan, HAN Fei-fei, TIAN Mei-ling, DUAN Ai-hong, KE Xiao-ning. Mechanisms of Resistance to PARP Inhibitor and Its Combination Therapy Strategies to Improve Sensitivity in Ovarian Cancer[J]. Journal of International Obstetrics and Gynecology, 2023, 50(5): 563-567.

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