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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 12 Pg. 3098-106 (Dec 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 25253779 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase 1
• MAP2K1 protein, human

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics, metabolism)
• DNA Mutational Analysis
• Disease Models, Animal
• Female
• Humans
• Inhibitory Concentration 50
• MAP Kinase Kinase 1 (antagonists & inhibitors, genetics)
• Male
• Mice
• Middle Aged
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mutation
• Neoplasm Staging
• Phosphorylation
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Stomach Neoplasms (drug therapy, genetics, pathology)
• Tumor Burden (drug effects, genetics)
• Xenograft Model Antitumor Assays