O'Sullivan Coyne Geraldine, Chen Alice P, Meehan Robert, Doroshow James H
Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, 31 Center Drive, Room 3A44, Bethesda, MD, 20892, USA.
Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Drugs. 2017 Feb;77(2):113-130. doi: 10.1007/s40265-016-0688-7.
The repair of DNA damage is a critical cellular process governed by multiple biochemical pathways that are often found to be defective in cancer cells. The poly(ADP-ribose) polymerase (PARP) family of proteins controls response to single-strand DNA breaks by detecting these damaged sites and recruiting the proper factors for repair. Blocking this pathway forces cells to utilize complementary mechanisms to repair DNA damage. While PARP inhibition may not, in itself, be sufficient to cause tumor cell death, inhibition of DNA repair with PARP inhibitors is an effective cytotoxic strategy when it is used in patients who carry other defective DNA-repair mechanisms, such as mutations in the genes BRCA 1 and 2. This discovery has supported the development of PARP inhibitors (PARPi), agents that have proven effective against various types of tumors that carry BRCA mutations. With the application of next-generation sequencing of tumors, there is increased interest in looking beyond BRCA mutations to identify genetic and epigenetic aberrations that might lead to similar defects in DNA repair, conferring susceptibility to PARP inhibition. Identification of these genetic lesions and the development of screening assays for their detection may allow for the selection of patients most likely to respond to this class of anticancer agents. This article provides an overview of clinical trial results obtained with PARPi and describes the companion diagnostic assays being established for patient selection. In addition, we review known mechanisms for resistance to PARPi and potential strategies for combining these agents with other types of therapy.
DNA损伤修复是一个关键的细胞过程，受多种生化途径调控，而这些途径在癌细胞中常常存在缺陷。聚（ADP - 核糖）聚合酶（PARP）家族蛋白通过检测这些受损位点并招募合适的修复因子来控制对单链DNA断裂的反应。阻断这一途径会迫使细胞利用互补机制来修复DNA损伤。虽然PARP抑制本身可能不足以导致肿瘤细胞死亡，但对于携带其他缺陷性DNA修复机制（如BRCA 1和2基因突变）的患者，使用PARP抑制剂抑制DNA修复是一种有效的细胞毒性策略。这一发现推动了PARP抑制剂（PARPi）的研发，这类药物已被证明对携带BRCA突变的各种类型肿瘤有效。随着肿瘤下一代测序技术的应用，人们越来越有兴趣超越BRCA突变，去识别可能导致类似DNA修复缺陷、使细胞对PARP抑制敏感的遗传和表观遗传异常。识别这些遗传损伤并开发用于检测它们的筛查试验，可能有助于选择最有可能对这类抗癌药物产生反应的患者。本文概述了使用PARPi获得的临床试验结果，并描述了正在建立的用于患者选择的伴随诊断试验。此外，我们还综述了已知的对PARPi耐药的机制以及将这些药物与其他类型治疗联合使用的潜在策略。
