Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy
Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy
复制标题
DOI：
10.1200/jco.18.02050
复制
发表时间：
2019-09-01
影响因子：
45.3
通讯作者：
Boulton, Simon J.
中科院分区：
文献类型：
--
作者：
Gourley, Charlie;Balmana, Judith;Boulton, Simon J.
DNA损伤反应（DDR）途径协调由内源性或外源性因素引起的DNA损伤的鉴定、信号传导和修复，并通过DNA修复调节细胞周期进程以最小化通过细胞分裂永久传递的DNA损伤。无法修复的严重DNA损伤可能引发细胞凋亡;因此，DDR途径作为癌症靶点至关重要。聚（ADP-核糖）聚合酶（PARP）是DDR中最知名的成分，几种PARP抑制剂已获得许可。然而，大约有450种蛋白质参与DDR，其中一些其他靶点正在实验室和临床上进行研究。我们回顾了PARP抑制剂在乳腺癌和卵巢癌中的临床效果的最新证据，并探讨了一线治疗和其他肿瘤类型的扩展。我们对患者选择技术的证据进行了评论，并总结了PARP抑制剂耐药机制的已知信息。然后，我们讨论了什么是已知的临床前的基本原理，针对其他成员的DDR途径和相关的肿瘤细胞遗传学，可能会赋予这些药物的敏感性。例子包括DNA损伤传感器（MLH 1）、损伤信号分子（共济失调-毛细血管扩张突变;共济失调-毛细血管扩张突变相关和Rad 3相关; CHK 1/2; DNA依赖性蛋白激酶，催化亚基; WEE 1; CDC 7）或修复效应蛋白（POLQ [也称为POL theta]、RAD 51、聚[ADP-核糖]糖水解酶）。针对这些分子中的一些分子，无论是作为一个单一的代理或组合的早期临床试验进行了讨论。最后，我们概述了必须解决的挑战，以最大限度地提高针对DDR提供的治疗机会。
The DNA damage response (DDR) pathway coordinates the identification, signaling, and repair of DNA damage caused by endogenous or exogenous factors and regulates cell-cycle progression with DNA repair to minimize DNA damage being permanently passed through cell division. Severe DNA damage that cannot be repaired may trigger apoptosis; as such, the DDR pathway is of crucial importance as a cancer target. Poly (ADP-ribose) polymerase (PARP) is the best-known element of the DDR, and several PARP inhibitors have been licensed. However, there are approximately 450 proteins involved in DDR, and a number of these other targets are being investigated in the laboratory and clinic. We review the most recent evidence for the clinical effect of PARP inhibition in breast and ovarian cancer and explore expansion into the first-line setting and into other tumor types. We critique the evidence for patient selection techniques and summarize what is known about mechanisms of PARP inhibitor resistance. We then discuss what is known about the preclinical rationale for targeting other members of the DDR pathway and the associated tumor cell genetics that may confer sensitivity to these agents. Examples include DNA damage sensors (MLH1), damage signaling molecules (ataxia-telangiectasia mutated; ataxia-telangiectasia mutated-related and Rad3-related; CHK1/2; DNA-dependent protein kinase, catalytic subunit; WEE1; CDC7), or effector proteins for repair (POLQ [also referred to as POL theta], RAD51, poly [ADP-ribose] glycohydrolase). Early-phase clinical trials targeting some of these molecules, either as a single agent or in combination, are discussed. Finally, we outline the challenges that must be addressed to maximize the therapeutic opportunity that targeting DDR provides.