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

13 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

Fingerprint

Mitogen-Activated Protein Kinase Kinases
Stomach Neoplasms
Mutation
Cell Line
Genes
Neoplasms
Phosphorylation
erbB-1 Genes
Growth
Oncogenes
Sequence Analysis
Histology
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

Sogabe, S., Togashi, Y., Kato, H., Kogita, A., Mizukami, T., Sakamoto, Y., ... 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

MEK inhibitor for gastric cancer with MEK1 gene mutations. / Sogabe, Shunsuke; Togashi, Yosuke; Kato, Hiroaki; Kogita, Akihiro; Mizukami, Takuro; Sakamoto, Yoichi; Banno, Eri; Terashima, Masato; Hayashi, Hidetoshi; De Velasco, Marco A.; Sakai, Kazuko; Fujita, Yoshihiko; Tomida, Shuta; Yasuda, Takushi; Takeyama, Yoshifumi; Okuno, Kiyotaka; Nishio, Kazuto.

In: Molecular Cancer Therapeutics, Vol. 13, No. 12, 01.12.2014, p. 3098-3106.

Research output: Contribution to journalArticle

Sogabe, S, Togashi, Y, Kato, H, Kogita, A, Mizukami, T, Sakamoto, Y, Banno, E, Terashima, M, Hayashi, H, De Velasco, MA, 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, vol. 13, no. 12, pp. 3098-3106. https://doi.org/10.1158/1535-7163.MCT-14-0429
Sogabe S, Togashi Y, Kato H, Kogita A, Mizukami T, Sakamoto Y et al. MEK inhibitor for gastric cancer with MEK1 gene mutations. Molecular Cancer Therapeutics. 2014 Dec 1;13(12):3098-3106. https://doi.org/10.1158/1535-7163.MCT-14-0429
Sogabe, Shunsuke ; Togashi, Yosuke ; Kato, Hiroaki ; Kogita, Akihiro ; Mizukami, Takuro ; Sakamoto, Yoichi ; Banno, Eri ; Terashima, Masato ; Hayashi, Hidetoshi ; De Velasco, Marco A. ; Sakai, Kazuko ; Fujita, Yoshihiko ; Tomida, Shuta ; Yasuda, Takushi ; Takeyama, Yoshifumi ; Okuno, Kiyotaka ; Nishio, Kazuto. / MEK inhibitor for gastric cancer with MEK1 gene mutations. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 12. pp. 3098-3106.
@article{57830d6e90704a3ca84a9cacef50a74c,
title = "MEK inhibitor for gastric cancer with MEK1 gene mutations",
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.",
author = "Shunsuke Sogabe and Yosuke Togashi and Hiroaki Kato and Akihiro Kogita and Takuro Mizukami and Yoichi Sakamoto and Eri Banno and Masato Terashima and Hidetoshi Hayashi and {De Velasco}, {Marco A.} and Kazuko Sakai and Yoshihiko Fujita and Shuta Tomida and Takushi Yasuda and Yoshifumi Takeyama and Kiyotaka Okuno and Kazuto Nishio",
year = "2014",
month = "12",
day = "1",
doi = "10.1158/1535-7163.MCT-14-0429",
language = "English",
volume = "13",
pages = "3098--3106",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - MEK inhibitor for gastric cancer with MEK1 gene mutations

AU - Sogabe, Shunsuke

AU - Togashi, Yosuke

AU - Kato, Hiroaki

AU - Kogita, Akihiro

AU - Mizukami, Takuro

AU - Sakamoto, Yoichi

AU - Banno, Eri

AU - Terashima, Masato

AU - Hayashi, Hidetoshi

AU - De Velasco, Marco A.

AU - Sakai, Kazuko

AU - Fujita, Yoshihiko

AU - Tomida, Shuta

AU - Yasuda, Takushi

AU - Takeyama, Yoshifumi

AU - Okuno, Kiyotaka

AU - Nishio, Kazuto

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84918549511&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84918549511&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-14-0429

DO - 10.1158/1535-7163.MCT-14-0429

M3 - Article

VL - 13

SP - 3098

EP - 3106

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 12

ER -