PARP抑制剂在上皮性卵巢癌中的耐药机制及解决策略

doi:10.12280/gjfckx.20230839

摘要/Abstract

摘要：

上皮性卵巢癌（epithelial ovarian cancer，EOC）的致死率在女性生殖系统恶性肿瘤中居首位。EOC的传统治疗方案是肿瘤细胞减灭术联合铂类药物为基础的化疗，但2年内仍有约70%的患者复发或耐药。多腺苷二磷酸核糖聚合酶[poly (ADP-ribose) polymerase，PARP]抑制剂通过对乳腺癌相关基因（breast cancer-related gene，BRCA）突变的肿瘤细胞发挥合成致死效应，为EOC提供了全新的治疗模式。PARP抑制剂为EOC靶向维持治疗带来重大突破，然而仍有患者在治疗中逐步耐药，主要的耐药机制包括同源重组修复途径恢复、药物靶点变化和致死性DNA损伤减少，目前的解决策略包括PARP抑制剂联合DNA损伤修复抑制剂、联合抑制同源重组修复通路的药物、联合传统抗癌方案、联合P-糖蛋白（P-glucoprotein，P-gp）抑制剂以及更换其他类型的PARP抑制剂。

关键词: 多（ADP核糖）聚合酶抑制剂, 卵巢肿瘤, 肿瘤, 腺和上皮, 同源重组, 基因, BRCA1, 基因, BRCA2, 药物疗法

Abstract:

The fatality rate of epithelial ovarian cancer (EOC) ranks first among malignant tumors of the female reproductive system. The traditional treatment approach for EOC involves cytoreductive surgery combined with platinum-based chemotherapy. However, within 2 years, approximately 70% of patients experience relapse or develop resistance. Poly (ADP-ribose) polymerase (PARP) inhibitors, as a novel molecular targeted drug, exert the "synthetic-lethal" effect on tumor cells with breast cancer-related gene (BRCA) mutations, offering a brand-new therapeutic model for EOC. PARP inhibitors have brought significant breakthroughs in targeted maintenance therapy for EOC. However, some patients still gradually fail to respond to PARP inhibitors, and the main resistance mechanisms include homologous recombination repair (HRR) recovery, drug target changes, and reduction of fatal DNA damage. Current strategies to improve its sensitivity include combining with DNA damage repair inhibitors, drugs that inhibit the HRR pathway, traditional anticancer regimens, P-glucoprotein (P-gp) inhibitors, and replacing alternative types of PARP inhibitors.

Key words: Poly(ADP-ribose) polymerase inhibitors, Ovarian neoplasms, Neoplasms, glandular and epithelial, Homologous recombination, Genes, BRCA1, Genes, BRCA2, Drug therapy

张文洋, 汪希鹏. PARP抑制剂在上皮性卵巢癌中的耐药机制及解决策略[J]. 国际妇产科学杂志, 2024, 51(1): 52-59.

ZHANG Wen-yang, WANG Xi-peng. Mechanisms of Resistance to PARP Inhibitor and Strategies to Improve Its Sensitivity in Epithelial Ovarian Cancer[J]. Journal of International Obstetrics and Gynecology, 2024, 51(1): 52-59.

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