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

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

Kim HJ1,2,3, Kang SK1,2, Kwon WS1,2, Kim TS1,2, Jeong I1,2,3, Jeung HC1,2,4, Kragh M5, Horak ID5, Chung HC1,2,3,4, Rha SY1,2,3,4.

Author information

1
Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea.
2
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
3
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
4
Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
5
Symphogen A/S, Ballerup, Denmark.

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

PMID:
29435981
DOI:
10.1002/ijc.31304

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