Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma Journal Article

Authors: Marks, J. L.; Gong, Y.; Chitale, D.; Golas, B.; McLellan, M. D.; Kasai, Y.; Ding, L.; Mardis, E. R.; Wilson, R. K.; Solit, D.; Levine, R.; Michel, K.; Thomas, R. K.; Rusch, V. W.; Ladanyi, M.; Pao, W.
Article Title: Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma
Abstract: Genetic lesions affecting a number of kinases and other elements within the epidermal growth factor receptor (EGFR) signaling pathway have been implicated in the pathogenesis of human non-small-cell lung cancer (NSCLC). We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this pathway that could contribute to lung tumorigenesis. We have identified in 2 of 207 primary lung tumors a somatic activating mutation in exon 2 of MEK1 (i.e., mitogen-activated protein kinase kinase 1 or MAP2K1) that substitutes asparagine for lysine at amino acid 57 (K57N) in the nonkinase portion of the kinase. Neither of these two tumors harbored known mutations in other genes encoding components of the EGFR signaling pathway (i.e., EGFR, HER2, KRAS, PIK3CA, and BRAF). Expression of mutant, but not wild-type, MEK1 leads to constitutive activity of extracellular signal-regulated kinase (ERK)-1/2 in human 293T cells and to growth factor-independent proliferation of murine Ba/F3 cells. A selective MEK inhibitor, AZD6244, inhibits mutant-induced ERK activity in 293T cells and growth of mutant-bearing Ba/F3 cells. We also screened 85 NSCLC cell lines for MEK1 exon 2 mutations; one line (NCI-H1437) harbors a Q56P substitution, a known transformation-competent allele of MEK1 originally identified in rat fibroblasts, and is sensitive to treatment with AZD6244. MEK1 mutants have not previously been reported in lung cancer and may provide a target for effective therapy in a small subset of patients with lung adenocarcinoma. ©2008 American Association for Cancer Research.
Keywords: signal transduction; controlled study; gene mutation; human cell; genetics; mutation; molecular genetics; polymerase chain reaction; adenocarcinoma; cell proliferation; mouse; animal; metabolism; animals; mice; mitogen activated protein kinase kinase 1; lung non small cell cancer; lung neoplasms; epidermal growth factor receptor; receptor, epidermal growth factor; mutational analysis; carcinogenesis; lung tumor; gene expression regulation; gene expression regulation, neoplastic; lung adenocarcinoma; amino acid sequence; molecular sequence data; sequence homology, amino acid; nucleotide sequence; dna mutational analysis; sequence homology; 5 (4 bromo 2 chloroanilino) 4 fluoro 1 methyl 1h benzimidazole 6 carbohydroxamic acid 2 hydroxyethyl ester; map kinase kinase 1; gene expression regulation, enzymologic; map2k1 protein, human
Journal Title: Cancer Research
Volume: 68
Issue: 14
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2008-07-15
Start Page: 5524
End Page: 5528
Language: English
DOI: 10.1158/0008-5472.can-08-0099
PUBMED: 18632602
PROVIDER: scopus
PMCID: PMC2586155
Notes: --- - "Cited By (since 1996): 36" - "Export Date: 17 November 2011" - "CODEN: CNREA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Valerie W Rusch
    651 Rusch
  2. David Solit
    431 Solit
  3. William Pao
    141 Pao
  4. Dhananjay Arun Chitale
    33 Chitale
  5. Marc Ladanyi
    861 Ladanyi
  6. Ross Levine
    469 Levine
  7. Yixuan Gong
    15 Gong
  8. Benjamin Jon Golas
    5 Golas
  9. Jenifer Lynn Marks
    14 Marks