Carcinogenesis Advance Access originally published online on April 20, 2009
Carcinogenesis 2009 30(7):1097-1105; doi:10.1093/carcin/bgp097
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Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells
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
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/Fax: +81 52 764 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 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.
Abbreviations: EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FCS, fetal calf serum; HGF, hepatocyte growth factor; MM, malignant mesothelioma; MPM, malignant pleural mesothelioma; mRNA, messenger RNA; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PDGFR, platelet-derived growth factor receptor; PI3-K, phosphoinositide 3-kinase; RTK, receptor tyrosine kinase; sh, short hairpin; TKI, tyrosine kinase inhibitor
Received October 11, 2008; revised April 13, 2009; accepted April 16, 2009.