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Identification of c-Src as a potential therapeutic target for gastric cancer and of MET activation as a cause of resistance to c-Src inhibition.

Authors
  • Okamoto, Wataru
  • Okamoto, Isamu
  • Yoshida, Takeshi
  • Okamoto, Kunio
  • Takezawa, Ken
  • Hatashita, Erina
  • Yamada, Yuki
  • Kuwata, Kiyoko
  • Arao, Tokuzo
  • Yanagihara, Kazuyoshi
  • Fukuoka, Masahiro
  • Nishio, Kazuto
  • Nakagawa, Kazuhiko
Type
Published Article
Journal
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research
Publication Date
May 01, 2010
Volume
9
Issue
5
Pages
1188–1197
Identifiers
DOI: 10.1158/1535-7163.MCT-10-0002
PMID: 20406949
Source
Medline
License
Unknown

Abstract

Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G(1) arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G(1) arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors.

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