Journal Article

Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells

Koji Kawaguchi, Hideki Murakami, Tetsuo Taniguchi, Makiko Fujii, Shigehisa Kawata, Takayuki Fukui, Yutaka Kondo, Hirotaka Osada, Noriyasu Usami, Kohei Yokoi, Yuichi Ueda, Yasushi Yatabe, Masafumi Ito, Yoshitsugu Horio, Toyoaki Hida and Yoshitaka Sekido

in Carcinogenesis

Volume 30, issue 7, pages 1097-1105
Published in print July 2009 | ISSN: 0143-3334
Published online April 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp097
Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells

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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-β. 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.

Journal Article.  6412 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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