EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition

Takuro Mizukami, Yosuke Togashi, Shunsuke Sogabe, Eri Banno, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Kazuto Nishio

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Since the prognosis of unresectable advanced gastric cancer remains poor, novel therapeutic strategies are needed. Somatic MEK1 gene mutations have been reported as oncogenic activating mutations in gastric cancer, and MEK inhibitors can be effective against such gastric cancers. In the present study, however, activated EGFR and HER2 signals after treatment with a MEK inhibitor (trametinib) were found in a MEK1-mutated gastric cancer cell line (OCUM-1 cell line) using a phospho-receptor tyrosine kinase array. The phosphorylation of EGFR and HER2 reactivated ERK1/2, which had been inhibited by trametinib, and EGF stimulation led to resistance to trametinib in this cell line. Lapatinib, an EGFR and an HER2 inhibitor, reversed the activation of ERK1/2 by inhibiting the phosphorylation of EGFR and HER2 and cancelled the resistance. The combination of trametinib and lapatinib synergistically inhibited the cell growth of the OCUM-1 cell line and strongly induced apoptosis by inhibiting the activated EGFR and HER2 signals. These results suggest that the EGFR and HER2 signals play a salvage role and are related to resistance to MEK inhibitors in MEK1-mutated gastric cancer. Moreover, combination therapy with trametinib and lapatinib can exhibit a synergistic effect and may contribute to overcoming the resistance to MEK inhibitors.

Original languageEnglish
Pages (from-to)499-505
Number of pages7
JournalInternational journal of oncology
Volume47
Issue number2
DOIs
Publication statusPublished - Aug 1 2015
Externally publishedYes

Keywords

  • EGFR
  • Gastric cancer
  • HER2
  • MEK inhibitor
  • MEK1 mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Mizukami, T., Togashi, Y., Sogabe, S., Banno, E., Terashima, M., De Velasco, M. A., Sakai, K., Fujita, Y., Tomida, S., Nakajima, T. E., Boku, N., & Nishio, K. (2015). EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition. International journal of oncology, 47(2), 499-505. https://doi.org/10.3892/ijo.2015.3050