Reversal of c-MET-mediated Resistance to Cytotoxic Anticancer Drugs by a Novel c-MET Inhibitor TAS-115

Eiji Kunii; Hiroaki Ozasa; Tetsuya Oguri; Ken Maeno; Satoshi Fukuda; Takehiro Uemura; Osamu Takakuwa; Hirotsugu Ohkubo; Masaya Takemura; Akio Niimi

Reversal of c-MET-mediated Resistance to Cytotoxic Anticancer Drugs by a Novel c-MET Inhibitor TAS-115

Anticancer Res. 2015 Oct;35(10):5241-7.

Authors

Affiliations

¹ Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan.
² Department of Multidisciplinary Cancer Treatment, Graduate School of Medicine Kyoto University, Sakyo-ku, Kyoto, Japan.
³ Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan t-oguri@med.nagoya-cu.ac.jp.

PMID: 26408683

Abstract

Background: The cellular N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (c-MET) protein is the receptor tyrosine kinase for hepatocyte growth factor. We recently found that c-MET protein expression and activation were enhanced in the majority of small cell lung cancer cell lines with cytotoxic anticancer drug resistance, and that down-regulation of c-MET reduced resistance to these drugs.

Materials and methods: Expression of c-MET was studied in three non-small cell lung cancer (NSCLC) cell lines, including six resistant cell strains to cytotoxic anticancer drugs. To assess the effect of c-MET activation on drug resistance, we studied drug sensitivity in the presence of a novel c-MET inhibitor TAS-115.

Results: c-MET expression and activation are also enhanced in some cytotoxic anticancer drug-resistant NSCLC cell lines, and inhibition of c-MET activation by TAS-115 reduced resistance of these cell lines to anticancer drugs.

Conclusion: The mechanism of cellular resistance to anticancer drugs via hepatocyte growth factor/c-MET signal activation is not restricted to small cell lung cancer cell lines, and TAS-115 might be able to reverse the drug resistance of these cancer cells.

Keywords: Lung cancer; TAS-115; anticancer drug combinations; c-MET inhibitor; drug resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / therapeutic use
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects*
Hepatocyte Growth Factor / metabolism
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / metabolism*
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-met / antagonists & inhibitors
Proto-Oncogene Proteins c-met / metabolism*
Quinolines / pharmacology*
Small Cell Lung Carcinoma / drug therapy
Small Cell Lung Carcinoma / metabolism*
Thiourea / analogs & derivatives*
Thiourea / pharmacology

Substances

Antineoplastic Agents
HGF protein, human
Protein Kinase Inhibitors
Quinolines
Hepatocyte Growth Factor
MET protein, human
Proto-Oncogene Proteins c-met
Thiourea
4-(2-fluoro-4-((((2-phenylacetyl)amino)thioxomethyl)amino)phenoxy)-7-methoxy-N-methyl-6-quinolinecarboxamide