Lord Christopher J, Ashworth Alan
The Cancer Research UK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
University of California, San Francisco (UCSF), Helen Diller Family Comprehensive Cancer Center, 1450 Third Street, San Francisco, CA 94158, USA.
Science. 2017 Mar 17;355(6330):1152-1158. doi: 10.1126/science.aam7344. Epub 2017 Mar 16.
PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either or are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.
聚（ADP - 核糖）聚合酶抑制剂（PARPi）是一种针对聚（ADP - 核糖）聚合酶的癌症治疗药物，是首个临床获批的旨在利用合成致死性的药物，合成致死性是近一个世纪前提出的一个遗传学概念。携带BRCA1或BRCA2种系突变的患者所患肿瘤对PARPi敏感，因为它们具有特定类型的DNA修复缺陷。PARPi在具有这种修复缺陷的更常见癌症中也显示出有前景的活性。然而，与其他靶向治疗一样，晚期疾病会出现对PARPi的耐药性。此外，在联合用药方法中确定PARPi的最佳使用方式一直具有挑战性。尽管如此，PARPi合成致死性的临床前发现以及临床获批途径为其他疗法的开发提供了有趣的经验教训。在此，我们讨论关于PARP抑制剂的当前知识以及最大化其临床疗效的潜在方法。
