BRCA1 Mutation: A Predictive Marker for Radiation Therapy?
BRCA1 Mutation: A Predictive Marker for Radiation Therapy?
复制标题
DOI：
10.1016/j.ijrobp.2015.05.037
复制
发表时间：
2015-10-01
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Kan C;Zhang J
DNA修复，特别是DNA双链断裂（DSBs）修复，对于正常细胞和癌细胞的存活都是至关重要的。为了有效地修复受损的DNA，一种复杂的修复机制已经在细胞中发展起来。主要参与dsb修复的途径是同源重组（HR）和经典非同源末端连接（cNHEJ），尽管第三种dsb修复途径NHEJ （aNHEJ）在某些情况下也可能很重要。由肿瘤抑制基因BRCA1编码的BRCA1蛋白调控所有dsb修复通路。鉴于dsb是电离辐射（IR）引起的最具生物学意义的病变，而dsb修复受损会导致辐射敏感性，因此预计BRCA1突变的癌症患者应该从放射治疗（RT）中受益。然而，临床数据是相互矛盾和不确定的。在这里，我们概述了在实验模型和临床研究中关于BRCA1缺陷和RT敏感性的数据现状。此外，我们将讨论通过聚（ADP核糖）聚合酶（PARP）抑制剂来增强RT效果的策略，这些药物正在作为BRCA 1/2突变患者的单药治疗进行研究。
DNA repair, particularly DNA double strand breaks (DSBs) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells in order to efficiently repair the damaged DNA. The pathways that are predominately involved in DSBs repair are homologous recombination (HR) and classical nonhomologous end-joining (cNHEJ) although alternative NHEJ (aNHEJ), a third DSBs repair pathway, may also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSBs repair pathways. Given the fact that DSBs represent the most biologically significant lesions induced by ionizing radiation (IR) and impaired DSBs repair leads to radiation sensitivity it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy (RT). However, the clinical data are conflicting and inconclusive. Here, we provide an overview about the current status of the data regarding BRCA1 deficiency and RT sensitivity in both experimental models and clinical investigations. In addition, we will discuss a strategy to potentiate the effects of RT by poly(ADP ribose) polymerase (PARP) inhibitors, the pharmacologic drugs that are being investigated as a monotherapy for the treatment of patients with BRCA 1/2 mutations.