Significance of c-MET overexpression in cytotoxic anticancer drug-resistant small-cell lung cancer cells.
The c-MET receptor tyrosine kinase is the receptor for hepatocyte growth factor. Recently, activation of the c-MET/hepatocyte growth factor signaling pathway was associated with poor prognosis in various solid tumors and was one of the mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib. But the link between c-MET activation and the cytotoxic anticancer drug has not been fully examined. Here, we found that the enhanced expression and activation of c-MET in cytotoxic anticancer agent-resistant small-cell lung cancer cells. Downregulation of c-MET expression by siRNA against the c-MET gene or inhibition of c-MET activation by SU11274, a c-MET inhibitor, in the resistant cells altered resistance to the cytotoxic anticancer agent. These results indicated that c-MET overexpression might play an important role in acquired resistance to cytotoxic anticancer drugs. Furthermore, the number of c-MET gene loci was increased in the resistant cells compared to the parental cells. In conclusion, increased c-Met expression through an increase in the number of c-MET gene loci is one of the mechanisms of acquired resistance to cytotoxic anticancer drugs. Our results add a new strategy, the targeting of c-MET, for overcoming resistance to cytotoxic agents in small-cell lung cancer.
Department of Medical Oncology and Immunology, Nagoya City University, Nagoya, Japan; Department of Multidisciplinary Cancer Treatment, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Hiroaki
H
Ozasa
Tetsuya
T
Oguri
Ken
K
Maeno
Osamu
O
Takakuwa
Eiji
E
Kunii
Yoshitaka
Y
Yagi
Takehiro
T
Uemura
Daishi
D
Kasai
Mikinori
M
Miyazaki
Akio
A
Niimi
D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D034741:RNA, Small Interfering; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
c-MET inhibitor; c-MET overexpression; drug resistance; gene amplification; lung cancer