Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells
Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells
复制标题
DOI：
10.1093/carcin/bgp097
复制
发表时间：
2009-07-01
期刊：
影响因子：
4.7
通讯作者：
Sekido, Yoshitaka
中科院分区：
文献类型：
--
作者：
Kawaguchi, Koji;Murakami, Hideki;Sekido, Yoshitaka
恶性胸膜间皮瘤(MPM)是一种与石棉接触相关的侵袭性肿瘤。尽管包括MET在内的受体酪氨酸激酶(RTK)在大多数MPM中的表达和激活已被报道，但特异性的RTK抑制剂在MPM细胞中的反应低于预期。为了确定MET抑制剂缺乏反应是否是由于与其他RTK的协同作用，我们检测了MET和其他RTK的激活状态，包括由20个MPM细胞株组成的表皮生长因子受体(EGFR)家族，并测试了双重RTK抑制是否是一种有效的治疗策略。我们在14个(70%)和13个(65%)细胞系中检测到MET表达上调和磷酸化(从而表明激活)，但MET特异性抑制剂处理在大多数细胞系中显示出微弱或适度的抑制作用。磷酸化RTK阵列分析表明，MET与其他RTK同时激活，包括EGFR、ErbB2、ErbB3和血小板衍生生长因子受体-β。MET和EGFR抑制剂联合应用对MPM细胞增殖和侵袭的抑制作用比单独使用更强。这些结果表明，RTKs的共激活在间皮瘤细胞的增殖和/或生存中是必不可少的，因此，同时抑制RTKs可能是发展MPM分子靶向治疗的更有效的策略。
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm associated with asbestos exposure. Although expression and activation of receptor tyrosine kinases (RTKs), including MET, have been reported in most MPM, specific RTK inhibitors showed less than the expected response in MPM cells. To determine whether the lack of response of MET inhibitors was due to cooperation with other RTKs, we determined activation status of MET and other RTKs, including epidermal growth factor receptor (EGFR) family of 20 MPM cell lines, and tested whether dual RTK inhibition is an effective therapeutic strategy. We detected MET upregulation and phosphorylation (thus indicating activation) in 14 (70%) and 13 (65%) cell lines, but treatment with MET-specific inhibitors showed weak or modest effect of suppression in most of the cell lines. Phospho-RTK array analysis revealed that MET was simultaneously activated with other RTKs, including EGFR, ErbB2, ErbB3 and platelet-derived growth factor receptor-beta. Combination of MET and EGFR inhibitors triggered stronger inhibition on cell proliferation and invasion of MPM cells than that of each in vitro. These results indicated that coactivation of RTKs was essential in mesothelioma cell proliferation and/or survival, thus suggesting that simultaneous inhibition of RTKs may be a more effective strategy for the development of molecular target therapy for MPM.