PARP inhibitors: Synthetic lethality in the clinic.
PARP inhibitors: Synthetic lethality in the clinic.
复制标题
DOI：
10.1126/science.aam7344
复制
发表时间：
2017-03-17
期刊：
影响因子：
--
通讯作者：
Ashworth A
中科院分区：
文献类型：
--
作者：
Lord CJ;Ashworth A
PARP抑制剂（PARPi）是一种靶向聚（ADP-核糖）聚合酶的癌症治疗药物，是第一种临床批准的药物，旨在利用合成致死性，这是近世纪前提出的遗传概念。在BRCA 1或BRCA 2中携带生殖系突变的患者中产生的肿瘤对PARPi敏感，因为它们具有特定类型的DNA修复缺陷。PARPi还在共享这种修复缺陷的更常见的癌症中显示出有希望的活性。然而，与其他靶向治疗一样，对PARPi的耐药性在晚期疾病中出现。此外，确定PARPi在药物组合方法中的最佳使用一直具有挑战性。然而，PARPi合成致死性的临床前发现和临床批准的途径为其他疗法的开发提供了有趣的经验教训。在这里，我们讨论了PARP抑制剂的现有知识和最大限度地提高其临床有效性的潜在方法。
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 BRCA1 or BRCA2 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.
登录
查看更多内容
影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
45.3
作者：
Fong, Peter C.;Yap, Timothy A.;Kaye, Stan B.
通讯作者：
Kaye, Stan B.
影响因子：
7.3
作者：
Barber, Louise J.;Sandhu, Shahneen;Ashworth, Alan
通讯作者：
Ashworth, Alan
影响因子：
11.5
作者：
Kim, Geoffrey;Ison, Gwynn;Pazdur, Richard
通讯作者：
Pazdur, Richard
影响因子：
168.9
作者：
Audeh, M. William;Carmichael, James;Tutt, Andrew
通讯作者：
Tutt, Andrew