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Carcinogenesis Advance Access published online on April 20, 2009
Carcinogenesis, doi:10.1093/carcin/bgp097
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Koji Kawaguchi1,2, Hideki Murakami1, Tetsuo Taniguchi2, Makiko Fujii1, Shigehisa Kawata1, Takayuki Fukui3, Yutaka Kondo1, Hirotaka Osada1, Noriyasu Usami2, Kohei Yokoi2, Yuichi Ueda2, Yasushi Yatabe4, Masafumi Ito5, Yoshitsugu Horio6, Toyoaki Hida6 and Yoshitaka Sekido6,*

1 Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
2 Department of Cardio-Thoracic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
3 Department of Thoracic Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
4 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
5 Department of Pathology, Japanese Red Cross Nagoya First Hospital, 3-35 Michishita-cho Nakamura-ku, Nagoya 453-8511, Japan
6 Department of Thoracic Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan

* To whom correspondence should be addressed. Tel: +81 52 754 2993; Fax: +81 52 754 2993; Email: ysekido{at}aichi-cc.jp

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 as an effective therapeutic strategy. We detected MET upregulation and phosphorylation (thus indicating activation) in 14 (70%) and 13 (65%), 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 (PDGFR)-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 co-activation 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.

Received October 11, 2008; revised April 13, 2009; accepted April 16, 2009.


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