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 language | English |
|---|---|
| Pages (from-to) | 3098-3106 |
| Number of pages | 9 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 13 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 1 2014 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
- Medicine(all)
Cite this
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 journal › Article
}
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.
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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 -