聚 ADP 核糖聚合酶抑制剂耐药机制及其治疗意义。
Poly-ADP-ribosyl-polymerase inhibitor resistance mechanisms and their therapeutic implications.
机构信息
David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA.
出版信息
Curr Opin Obstet Gynecol. 2019 Feb;31(1):12-17. doi: 10.1097/GCO.0000000000000517.
PURPOSE OF REVIEW
Poly-ADP-ribosyl-polymerase (PARP) inhibitors are an increasingly-utilized therapy in women with high-grade serous ovarian carcinoma, but tumor resistance to PARP inhibitor monotherapy is inevitable.
RECENT FINDINGS
PARP inhibitors have been most studied in patients with breast and ovarian cancers associated with deleterious germline BRCA1 or BRCA2 mutations, though their role has expanded to include use as maintenance therapy in women with platinum-sensitive high-grade serous ovarian cancer due to the high propensity of such cancers to have defects in DNA repair by homologous recombination. As mechanisms of PARP inhibitor resistance are elucidated, rationale combination strategies can be devised to extend therapeutic benefits and to abrogate resistance.
SUMMARY
Mechanisms of resistance include restoration of homologous recombination repair proficiency, loss of cancer cell reliance on PARP, and increased intracellular signaling through cell growth pathways.
目的综述
聚 ADP-核糖聚合酶（PARP）抑制剂在高级别浆液性卵巢癌女性中越来越多地被用作治疗方法，但肿瘤对 PARP 抑制剂单药治疗的耐药性是不可避免的。
最近的发现
PARP 抑制剂在与有害种系 BRCA1 或 BRCA2 突变相关的乳腺癌和卵巢癌患者中研究最多，尽管由于此类癌症同源重组 DNA 修复缺陷的高倾向，它们的作用已扩展到包括作为铂类敏感的高级别浆液性卵巢癌的维持治疗。随着 PARP 抑制剂耐药机制的阐明，可以设计合理的联合策略来延长治疗效果并消除耐药性。
总结
耐药机制包括同源重组修复能力的恢复、癌细胞对 PARP 的依赖丧失以及通过细胞生长途径增加细胞内信号。
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