Combined inhibition of MET and EGFR suppresses proliferation of malignant mesothelioma cells
| Autor: | Yasushi Yatabe, Kohei Yokoi, Yoshitaka Sekido, Koji Kawaguchi, Makiko Fujii, Hideki Murakami, Toyoaki Hida, Shigehisa Kawata, Tetsuo Taniguchi, Masafumi Ito, Noriyasu Usami, Yuichi Ueda, Takayuki Fukui, Yoshitsugu Horio, Yutaka Kondo, Hirotaka Osada |
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| Rok vydání: | 2009 |
| Předmět: |
Mesothelioma
Cancer Research Receptor ErbB-2 Pleural Neoplasms medicine.medical_treatment Biology Receptor tyrosine kinase Receptor Platelet-Derived Growth Factor beta Downregulation and upregulation Cell Line Tumor medicine Humans Neoplasm Invasiveness ERBB3 Epidermal growth factor receptor Phosphorylation Cell Proliferation EGFR inhibitors Cell growth Growth factor General Medicine Proto-Oncogene Proteins c-met medicine.disease Up-Regulation ErbB Receptors Cancer research biology.protein Signal Transduction |
| Zdroj: | Carcinogenesis. 30:1097-1105 |
| ISSN: | 1460-2180 0143-3334 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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