Department of Medical Oncology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, Japan.
Mol Cancer Ther. 2010 May;9(5):1188-97. doi: 10.1158/1535-7163.MCT-10-0002. Epub 2010 Apr 20.
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.
靶向 c-Src 的治疗策略有望应用于多种癌症。我们现在研究了达沙替尼（抑制 c-Src 和其他几种激酶活性）对细胞生长的影响以及人胃癌细胞系中达沙替尼耐药的机制。免疫印迹分析显示，在大多数检测的胃癌细胞系中，c-Src 在不同水平被激活。达沙替尼通过流式细胞术抑制细胞对细胞外信号调节激酶（ERK）的磷酸化并诱导 G1 期阻滞，在一些敏感细胞系中观察到这一现象。在其他敏感细胞系中，达沙替尼抑制 ERK 和 AKT 的磷酸化并诱导细胞凋亡，这表现为 caspase-3 活性增加和多聚（ADP-核糖）聚合酶的裂解。通过 RNA 干扰敲低 c-Src 也会诱导达沙替尼敏感细胞系中的 G1 期阻滞或凋亡，表明达沙替尼的抗增殖作用归因于 c-Src 的抑制。激活 MET 的胃癌细胞系对达沙替尼耐药。达沙替尼对 ERK 或 AKT 信号没有影响，而 MET 抑制剂 PHA-665752 则诱导这些细胞凋亡。对 c-Src 或 MET 抑制剂有反应的胃癌细胞亚群是不同的且不重叠的。我们的研究结果表明，c-Src 是治疗胃癌的一个有前途的靶点，分析 MET 扩增可能优化 c-Src 抑制剂治疗的患者选择。
