ATM Expression Predicts Veliparib and Irinotecan Sensitivity in Gastric Cancer by Mediating P53-Independent Regulation of Cell Cycle and Apoptosis
ATM Expression Predicts Veliparib and Irinotecan Sensitivity in Gastric Cancer by Mediating P53-Independent Regulation of Cell Cycle and Apoptosis
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DOI：
10.1158/1535-7163.mct-15-1002
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发表时间：
2016-12-01
影响因子：
5.7
通讯作者：
Yong, Wei Peng
中科院分区：
文献类型：
--
作者：
Subhash, Vinod Vijay;Tan, Shi Hui;Yong, Wei Peng
确定合成致死细胞靶点和协同药物组合在癌症化疗中很重要，因为它们有助于克服治疗耐药性和提高疗效。共济失调毛细血管扩张突变激酶（ATM）是一种核蛋白，在DNA损伤期间DNA修复信号和细胞周期检查点的启动中起主要作用。尽管ATM已被证明与胃癌预后不良相关，但其作为癌症化疗预测生物标志物的意义仍未被探索。本研究评估了atm诱导的合成致死率及其在胃癌细胞对PARP和TOP1抑制剂veliparib （ABT-888）和伊立替康（CPT-11）致敏中的作用。在一组胃细胞系中检测了ATM的表达，并测定了对每种抑制剂的IC50。在体外和体内还测定了ABT-888和CPT-11在胃癌细胞中的联合作用。发现ATM缺乏与对ABT-888和CPT-11单药治疗的敏感性增强有关，因此提示了一种合成致死机制。高ATM表达的细胞对单药治疗的敏感性降低；然而，ABT-888和CPT-11联合治疗显示出更高的疗效。此外，ATM表达被证明在细胞稳态中发挥重要作用，通过p53不依赖的方式调节细胞周期进程和凋亡。本研究强调了ATM表达作为胃癌细胞对PARP和TOP1抑制敏感性的预测标志物的临床应用，并为ATM依赖的细胞过程调节提供了更深入的机制见解。(c) 2016年aacr。
Identification of synthetically lethal cellular targets and synergistic drug combinations is important in cancer chemotherapy as they help to overcome treatment resistance and increase efficacy. The Ataxia Telangiectasia Mutated (ATM) kinase is a nuclear protein that plays a major role in the initiation of DNA repair signaling and cell-cycle check points during DNA damage. Although ATM was shown to be associated with poor prognosis in gastric cancer, its implications as a predictive biomarker for cancer chemotherapy remain unexplored. The present study evaluated ATM-induced synthetic lethality and its role in sensitization of gastric cancer cells to PARP and TOP1 inhibitors, veliparib (ABT-888) and irinotecan (CPT-11), respectively. ATM expression was detected in a panel of gastric cell lines, and the IC50 against each inhibitors was determined. The combinatorial effect of ABT-888 and CPT-11 in gastric cancer cells was also determined both in vitro and in vivo. ATM deficiency was found to be associated with enhanced sensitivity to ABT-888 and CPT-11 monotherapy, hence suggesting a mechanism of synthetic lethality. Cells with high ATM expression showed reduced sensitivity to monotherapy; however, they showed a higher therapeutic effect with ABT-888 and CPT-11 combinatorial therapy. Furthermore, ATM expression was shown to play a major role in cellular homeostasis by regulating cell-cycle progression and apoptosis in a P53-independent manner. The present study highlights the clinical utility of ATM expression as a predictive marker for sensitivity of gastric cancer cells to PARP and TOP1 inhibition and provides a deeper mechanistic insight into ATM-dependent regulation of cellular processes. (C) 2016 AACR.