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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jenifer L
authors.initials: JL
authors.lastname: Marks
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Gong
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Chitale
authors.forename: Ben
authors.initials: B
authors.lastname: Golas
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kasai
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.forename: Kathrin
authors.initials: K
authors.lastname: Michel
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Valerie W
authors.initials: VW
authors.lastname: Rusch
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D066246:ErbB Receptors; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human