Forty-nine gastric cancer cell lines with integrative genomic profiling for development of c-MET inhibitor

Int J Cancer. 2018 Jul 1;143(1):151-159. doi: 10.1002/ijc.31304. Epub 2018 Feb 23.

Abstract

Receptor tyrosine kinase MET (c-MET) has received considerable attention as a potential target for gastric cancer (GC) therapy and a number of c-MET inhibitors have been developed. For successful drug development, proper preclinical studies especially using patient derived cancer cell lines are very important. We profiled MET and MET-related characteristics in 49 GC cell lines to utilize them as models in preclinical studies of GC. Forty-nine cell lines were analyzed for genetic, biological, and molecular status to characterize MET and MET-related molecules. Four c-MET inhibitors were tested to elucidate the dependency on MET pathway in the 49 GC cell lines. Six of 49 cell lines were MET amplified with overexpression of c-MET and p-MET. The variants of MET were not associated with c-MET expression or amplification. Hs746T showed an exon 14 deletion in conjunction with MET amplification. The cell lines were divided into 6 MET amplified, 2 c-MET overexpressed, 2 hepatocyte growth factor (HGF) overexpressed, and 39 MET-negative subgroups. Except tivantinib, the c-MET inhibitors showed higher inhibition (%) in MET amplified than in MET nonamplified cell lines that MET amplified cell lines showed MET pathway dependency. However, the c-MET overexpressed and HGF overexpressed cell lines showed moderate dependency on MET pathway. Well-characterized cell lines are very important in studying drug development. Our 49 GC cell lines had various characteristics of MET and MET-related molecules and MET pathway dependency. These provide a promising platform for development of various RTK inhibitors including c-MET inhibitors.

Keywords: HGF; MET; cell line; gastric cancer; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Female
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hepatocyte Growth Factor / genetics*
  • Humans
  • Male
  • Middle Aged
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism*
  • Pyrrolidinones / pharmacology
  • Quinolines / pharmacology
  • Sequence Analysis, RNA
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Up-Regulation / drug effects
  • Whole Exome Sequencing

Substances

  • ARQ 197
  • HGF protein, human
  • Protein Kinase Inhibitors
  • Pyrrolidinones
  • Quinolines
  • Hepatocyte Growth Factor
  • MET protein, human
  • Proto-Oncogene Proteins c-met