Identification of c-Src as a Potential Therapeutic Target for Gastric Cancer and of MET Activation as a Cause of Resistance to c-Src Inhibition
Identification of c-Src as a Potential Therapeutic Target for Gastric Cancer and of MET Activation as a Cause of Resistance to c-Src Inhibition
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DOI：
10.1158/1535-7163.mct-10-0002
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发表时间：
2010-05-01
影响因子：
5.7
通讯作者：
Nakagawa, Kazuhiko
中科院分区：
文献类型：
--
作者：
Okamoto, Wataru;Okamoto, Isamu;Nakagawa, Kazuhiko
以c-Src为靶点的治疗策略有望用于多种癌症。我们现在研究了达沙替尼对人胃癌细胞株生长的影响以及达沙替尼耐药的机制。达沙替尼可以抑制c-Src和其他几种激酶的活性。免疫印迹分析显示，在所检测的大多数胃癌细胞系中都有不同程度的c-Src激活。流式细胞术显示，达沙替尼抑制了细胞外信号调节激酶(ERK)的磷酸化，并诱导了G(1)期停滞。在其他反应细胞系中，达沙替尼抑制ERK和AKT的磷酸化并诱导细胞凋亡，表现为caspase-3活性的增加和聚(ADP-核糖)聚合酶的裂解。RNA干扰去除c-Src还可诱导Dasatinib反应的细胞株发生G(1)期停滞或凋亡，提示Dasatinib的抗增殖作用与抑制c-Src有关。MET激活阳性的胃癌细胞株对达沙替尼耐药。达沙替尼对ERK或AKT信号转导无影响，而MET抑制剂PHA-665752可诱导细胞凋亡。通过对c-Src或MET抑制剂的反应确定的胃癌细胞亚群是不同的且不重叠的。我们的结果表明，c-Src是治疗胃癌的一个有前途的靶点，MET扩增分析可能会优化c-Src抑制剂治疗患者的选择。摩尔癌症治疗；9(5)；1188-97。(C)2010年AACR。
Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G(1) arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G(1) arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors. Mol Cancer Ther; 9(5); 1188-97. (C) 2010 AACR.