Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines
Low ATM protein expression and depletion of p53 correlates with olaparib sensitivity in gastric cancer cell lines
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DOI：
10.4161/cc.29212
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发表时间：
2014-07-01
期刊：
影响因子：
4.3
通讯作者：
Bebb, D. Gwyn
中科院分区：
文献类型：
--
作者：
Kubota, Eiji;Williamson, Christopher T.;Bebb, D. Gwyn
聚（ADP-核糖）聚合酶（PARP）的小分子抑制剂在治疗同源重组（HR）缺陷型肿瘤（如BRCA 1和BRCA 2缺陷型乳腺癌和卵巢癌）方面显示出相当大的前景。我们以前报道过，缺乏共济失调毛细血管扩张突变（ATM）的套细胞淋巴瘤细胞在体外和体内对PARP-1抑制剂敏感。在这里，我们报告说，PARP抑制剂可以潜在的目标ATM缺陷所产生的实体恶性肿瘤。我们发现ATM蛋白表达在胃癌细胞系之间存在差异，NUGC 4蛋白水平显著降低。ATM蛋白表达与对PARP抑制剂olaparib的敏感性之间存在显著相关性，NUGC 4最敏感。此外，使用小分子抑制剂（KU 55933）或shRNA介导的ATM蛋白耗竭降低ATM激酶活性可增强p53耗竭或失活胃癌细胞系中奥拉帕尼的敏感性。我们的研究结果表明，ATM是一个潜在的预测生物标志物的PARP-1抑制剂活性的胃癌窝藏破坏p53，ATM和PARP-1的联合抑制是一个合理的策略，扩大PARP-1抑制剂的效用与p53破坏胃癌。
Small-molecule inhibitors of poly (ADP-ribose) polymerase (PARP) have shown considerable promise in the treatment of homologous recombination (HR)-defective tumors, such as BRCA1- and BRCA2-deficient breast and ovarian cancers. We previously reported that mantle cell lymphoma cells with deficiency in ataxia telangiectasia mutated (ATM) are sensitive to PARP-1 inhibitors in vitro and in vivo. Here, we report that PARP inhibitors can potentially target ATM deficiency arising in a solid malignancy. We show that ATM protein expression varies between gastric cancer cell lines, with NUGC4 having significantly reduced protein levels. Significant correlation was found between ATM protein expression and sensitivity to the PARP inhibitor olaparib, with NUGC4 being the most sensitive. Moreover, reducing ATM kinase activity using a small-molecule inhibitor (KU55933) or shRNA-mediated depletion of ATM protein enhanced olaparib sensitivity in gastric cancer cell lines with depletion or inactivation of p53. Our results demonstrate that ATM is a potential predictive biomarker for PARP-1 inhibitor activity in gastric cancer harboring disruption of p53, and that combined inhibition of ATM and PARP-1 is a rational strategy for expanding the utility of PARP-1 inhibitors to gastric cancer with p53 disruption.