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Ref Type Journal Article
PMID (22327936)
Authors Choi YL, Soda M, Ueno T, Hamada T, Haruta H, Yamato A, Fukumura K, Ando M, Kawazu M, Yamashita Y, Mano H
Title Oncogenic MAP2K1 mutations in human epithelial tumors.
Journal Carcinogenesis
Vol 33
Issue 5
Date 2012 May
URL
Abstract Text The scirrhous subtype of gastric cancer is a highly infiltrative tumor with a poor outcome. To identify a transforming gene in this intractable disorder, we constructed a retroviral complementary DNA (cDNA) expression library from a cell line (OCUM-1) of scirrhous gastric cancer. A focus formation assay with the library and mouse 3T3 fibroblasts led to the discovery of a transforming cDNA, encoding for MAP2K1 with a glutamine-to-proline substitution at amino acid position 56. Interestingly, treatment with a MAP2K1-specific inhibitor clearly induced cell death of OCUM-1 but not of other two cells lines of scirrhous gastric cancer that do not carry MAP2K1 mutations, revealing the essential role of MAP2K1(Q56P) in the transformation mechanism of OCUM-1 cells. By using a next-generation sequencer, we further conducted deep sequencing of the MAP2K1 cDNA among 171 human cancer specimens or cell lines, resulting in the identification of one known (D67N) and four novel (R47Q, R49L, I204T and P306H) mutations within MAP2K1. The latter four changes were further shown to confer transforming potential to MAP2K1. In our experiments, a total of six (3.5%) activating mutations in MAP2K1 were thus identified among 172 of specimens or cell lines for human epithelial tumors. Given the addiction of cancer cells to the elevated MAP2K1 activity for proliferation, human cancers with such MAP2K1 mutations are suitable targets for the treatment with MAP2K1 inhibitors.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
MAP2K1 I204T missense gain of function MAP2K1 I204T lies within the protein kinase domain of the Map2k1 protein (UniProt.org). I204T confers a gain of function to the Map2k1 protein as indicated by transformation activity and increased phosphorylation of Erk1/2 in culture (PMID: 22327936).
MAP2K1 P306H missense gain of function MAP2K1 P306H lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P306H confers a gain of function to the Map2k1 protein as indicated by increased phosphorylation of Erk1/2 and modest transformation activity in culture (PMID: 22327936).
MAP2K1 Q56P missense gain of function MAP2K1 Q56P does not lie within any known functional domains of the Map2k1 protein (UniProt.org). Q56P confers a gain of function to the Map2k1 protein as indicated by increased kinase activity and the ability to transform cultured cells (PMID: 22327936, PMID: 7651428) and also demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091). Y
MAP2K1 R47Q missense gain of function MAP2K1 R47Q does not lie within any known functional domains of the Map2k1 protein (UniProt.org). R47Q results in increased phosphorylation of Erk and is transforming in cell culture (PMID: 22327936).
MAP2K1 R49L missense gain of function MAP2K1 R49L does not lie within any known functional domains of the Map2k1 protein (UniProt.org). R49L confers a gain of function to the Map2k1 protein as demonstrated by transforming ability in culture and in vivo, and phosphorylation of Erk1/2 (PMID: 22327936).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 Q56P stomach cancer sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) inhibited growth of a gastric cancer cell line that requires MAP2K1 Q56P and inhibited phosphorylation of ERK in these cells (PMID: 22327936). 22327936