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

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.

MET as resistance factor for afatinib therapy and motility driver in gastric cancer cells

“…The analysis of 49 gastric cancer cell lines revealed that MET amplification predicts the sensitivity to MET inhibitors. Six MET -amplified gastric cancer cell lines, amongst them Hs746T, were sensitive to both MET antibodies and MET TKIs in cell viability assays [35]. This study confirmed the earlier results from Smolen et al .…”

Gene Expression Profiling Identifies Akt as a Target for Radiosensitization in Gastric Cancer Cells

“…The SNU-series of cell lines were obtained from the Korean cell line bank, and the YCC-series represented cell lines that were established using samples from Korean GC patients at the Songdang Institute for Cancer Research (SICR, Yonsei University College of Medicine, Seoul, South Korea). Cells were incubated in RPMI supplemented with 10% heat inactivated fetal bovine serum, 1% penicillin/streptomycin at 37 • C in a 5% CO2 humidified atmosphere, following the institutional protocol (17).…”

“…To identify somatic mutations in TP53, KRAS, and PIK3CA, whole exome sequencing (WES) data of the 12 GC cell lines were obtained from the genome database of the SICR and the Yonsei University College of Medicine (Seoul, South Korea). Briefly, single nucleotide variants (SNVs) were evaluated using WES data as previously described (17).…”

Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors

“…However, abnormal expression of c-Met kinases in cells usually triggers the occurrence, invasion, and metastasis of various cancer diseases [4]. c-Met kinase has been found overexpressed in various cancer cells and has become an attractive target for cancer treatment [5,6]. Nowadays, developing small molecule c-Met kinase inhibitors has become a hotspot in the treatment of human cancer [7].…”