MEK inhibitor for gastric cancer with MEK1 gene mutations

Shunsuke Sogabe, Yosuke Togashi, Hiroaki Kato, Akihiro Kogita, Takuro Mizukami, Yoichi Sakamoto, Eri Banno, Masato Terashima, Hidetoshi Hayashi, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takushi Yasuda, Yoshifumi Takeyama, Kiyotaka Okuno, Kazuto Nishio

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The prognosis for patients with unresectable advanced or recurrent gastric cancer remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations, upon which the growth of cancer cells is dependent, is needed. In this study, we evaluated sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several gastric cancer cell lines in vitro and found three poorly differentiated gastric cancer cell lines that were hypersensitive to the inhibitors. The sequence analyses in these three cell lines revealed that one cell line had a novel MEK1 mutation, while the other two had previously reported KRAS and MEK1 mutations, respectively; the gene statuses of the other resistant cell lines were all wild-type. Experiments using MEK1 expression vectors demonstrated that the MEK1 mutations induced the phosphorylation of ERK1/2 and had a transforming potential, enhancing the tumorigenicity. The MEK inhibitor dramatically reduced the phosphorylation of ERK1/2 and induced apoptosis in the cell lines with MEK1 mutations. In vivo, tumor growth was also dramatically decreased by an inhibitor. One of the 46 gastric cancer clinical samples that were examined had a MEK1 mutation; this tumor had a poorly differentiated histology. Considering the addiction of cancer cells to active MEK1 mutations for proliferation, gastric cancer with such oncogenic MEK1 mutations might be suitable for targeted therapy with MEK inhibitors.

Original languageEnglish
Pages (from-to)3098-3106
Number of pages9
JournalMolecular cancer therapeutics
Volume13
Issue number12
DOIs
Publication statusPublished - Dec 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Sogabe, S., Togashi, Y., Kato, H., Kogita, A., Mizukami, T., Sakamoto, Y., Banno, E., Terashima, M., Hayashi, H., De Velasco, M. A., Sakai, K., Fujita, Y., Tomida, S., Yasuda, T., Takeyama, Y., Okuno, K., & Nishio, K. (2014). MEK inhibitor for gastric cancer with MEK1 gene mutations. Molecular cancer therapeutics, 13(12), 3098-3106. https://doi.org/10.1158/1535-7163.MCT-14-0429