Cancer Discov：特殊基因突变或可使肿瘤对特殊抗癌药物敏感

  近日，来自德克萨斯大学MD安德森癌症中心的研究人员通过研究发现，在许多类型癌症中常见的ARID1a的突变会打断癌细胞中DNA的损伤修复，从而使得癌症不断恶化；当治疗特定癌症时该基因或许就是癌细胞的致命弱点，相关研究发表于国际杂志Cancer Discovery上。
  文章中，研究者Guang Peng博士表示，ARID1a是一种富含AT的交互结构域蛋白1a，ARID1a往往和癌症进展直接相关，其可以使得某些肿瘤对PARP抑制类药物变得敏感，比如奥拉帕尼等药物，这些药物可以阻断癌细胞的DNA损伤修复途径；研究者发现，相比其它癌细胞而言，PARP抑制剂可以更加有效作用于ARID1a缺失的细胞，而基于当前的研究数据，研究者或许可以开发出靶向作用这些突变的癌细胞的新方法。
  ARID1a在许多癌症中会发生频繁地突变，而且其还是SWI/SNF复合物的组分，SWI/SNF复合物是一种特殊的蛋白，其可以重排组装蛋白质的结构—染色质，同时当DNA损伤时，该复合物对于染色质的结构重组也非常关键。当ARID1a缺失或突变时，癌细胞就会失去感应并纠正DNA损伤的能力。
  这项研究中，研究者首次揭示了ARID1a对于DNA损伤应答的重要性，当ARID1a同一种名为ATR的蛋白进行作用时就会帮助进行损伤部位DNA结构的重组，ATR蛋白在损伤修复中扮演着重要的作用。当缺失正常的ARID1a功能时，DNA损伤修复就不会有效地发挥作用，从而就会使癌细胞对阻断修复途径的疗法变得更加敏感，比如PARP抑制剂等。
  利用癌细胞系及小鼠模型，研究人员发现PARP抑制剂可以明显且有效地杀灭缺失ARID1a的癌细胞。而目前研究者需要鉴别出到底是ARID1a蛋白的哪一块区域对于DNA损伤应答和修复异常关键，而且并不是所有ARID1a突变的病人都会对PARP抑制剂敏感。后期研究人员还将进行更为深入的研究鉴别出新型途径来选择性地对ARID1a突变的细胞进行靶向作用，从而为开发治疗癌症的新型疗法提供帮助。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors
Cancer Discovery    doi: 10.1158/2159-8290.CD-14-0849
Jianfeng Shen1, Yang Peng2, Leizhen Wei3,4, Wei Zhang1, Lin Yang1,5, Li Lan3,4, Prabodh Kapoor6, Zhenlin Ju7, Qianxing Mo8, Ie-Ming Shih9, Ivan P. Uray1, Xiangwei Wu1, Powel H. Brown1, Xuetong Shen6, Gordon B. Mills2 and Guang Peng1,5,*
ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors.

SIGNIFICANCE: ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors. Cancer Discov; 5(7); 1–16. ©2015 AACR.