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

Wataru Okamoto, Isamu Okamoto, Takeshi Yoshida, Kunio Okamoto, Ken Takezawa, Erina Hatashita, Yuki Yamada, Kiyoko Kuwata, Tokuzo Arao, Kazuyoshi Yanagihara, Masahiro Fukuoka, Kazuto Nishio, Kazuhiko Nakagawa

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50 Citations (Scopus)

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 G1 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 G1 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.

Original languageEnglish
Pages (from-to)1188-1197
Number of pages10
JournalMolecular Cancer Therapeutics
Volume9
Issue number5
DOIs
Publication statusPublished - May 1 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Okamoto, W., Okamoto, I., Yoshida, T., Okamoto, K., Takezawa, K., Hatashita, E., Yamada, Y., Kuwata, K., Arao, T., Yanagihara, K., Fukuoka, M., Nishio, K., & Nakagawa, K. (2010). 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. Molecular Cancer Therapeutics, 9(5), 1188-1197. https://doi.org/10.1158/1535-7163.MCT-10-0002