Reference Detail

Ref Type Journal Article
PMID (18632602)
Authors Marks JL, Gong Y, Chitale D, Golas B, McLellan MD, Kasai Y, Ding L, Mardis ER, Wilson RK, Solit D, Levine R, Michel K, Thomas RK, Rusch VW, Ladanyi M, Pao W
Title Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma.
Journal Cancer research
Vol 68
Issue 14
Date 2008 Jul 15
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
MAP2K1 R47Q MEK inhibitor (Pan)
MAP2K1 P306H MEK inhibitor (Pan)
MAP2K1 L37P MEK1 Inhibitor
MAP2K1 Q58_E62del MEK1 Inhibitor
MAP2K1 G128D MEK1 Inhibitor
MAP2K1 S123T MEK inhibitor (Pan)
MAP2K1 R49L MEK1 Inhibitor
MAP2K1 F53S MEK1 Inhibitor
MAP2K1 S123T MEK1 Inhibitor
MAP2K1 R47Q MEK1 Inhibitor
MAP2K1 E120Q MEK inhibitor (Pan)
MAP2K1 K57N MEK inhibitor (Pan)
MAP2K1 V60M MEK1 Inhibitor
MAP2K1 Q56_V60del MEK inhibitor (Pan)
MAP2K1 E120Q MEK1 Inhibitor
MAP2K1 S218D MEK inhibitor (Pan)
MAP2K1 D65N MEK1 Inhibitor
MAP2K1 I204T MEK1 Inhibitor
MAP2K1 act mut MEK inhibitor (Pan)
MAP2K1 E203K MEK inhibitor (Pan)
MAP2K1 E144K MEK1 Inhibitor
MAP2K1 Q58_E62del MEK inhibitor (Pan)
MAP2K1 amp MEK1 Inhibitor
MAP2K1 E144K MEK inhibitor (Pan)
MAP2K1 K59del MEK1 Inhibitor
MAP2K1 Q56P MEK1 Inhibitor
MAP2K1 K59del MEK inhibitor (Pan)
MAP2K1 Q56P MEK inhibitor (Pan)
MAP2K1 K57C MEK inhibitor (Pan)
MAP2K1 V60M MEK inhibitor (Pan)
MAP2K1 Y130C MEK1 Inhibitor
MAP2K1 D67N MEK1 Inhibitor
MAP2K1 Q56_V60del MEK1 Inhibitor
MAP2K1 F53_Q58del MEK inhibitor (Pan)
MAP2K1 K57C MEK1 Inhibitor
MAP2K1 L37P MEK inhibitor (Pan)
MAP2K1 F53L MEK1 Inhibitor
MAP2K1 I204T MEK inhibitor (Pan)
MAP2K1 D65N MEK inhibitor (Pan)
MAP2K1 S218D MEK1 Inhibitor
MAP2K1 F53S MEK inhibitor (Pan)
MAP2K1 Y130C MEK inhibitor (Pan)
MAP2K1 amp MEK inhibitor (Pan)
MAP2K1 F53L MEK inhibitor (Pan)
MAP2K1 T28I MEK1 Inhibitor
MAP2K1 F129L MEK inhibitor (Pan)
MAP2K1 F129L MEK1 Inhibitor
MAP2K1 G128D MEK inhibitor (Pan)
MAP2K1 act mut MEK1 Inhibitor
MAP2K1 F53_Q58del MEK1 Inhibitor
MAP2K1 D67N MEK inhibitor (Pan)
MAP2K1 E203K MEK1 Inhibitor
MAP2K1 R49L MEK inhibitor (Pan)
MAP2K1 P306H MEK1 Inhibitor
MAP2K1 T28I MEK inhibitor (Pan)
MAP2K1 K57N MEK1 Inhibitor
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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
K57N missense gain of function MAP2K1 K57N does not lie within any known functional domains of the Map2k1 protein (UniProt.org). K57N confers a gain of function on the Map2k1 protein as demonstrated by increased autophosphorylation (PMID: 29753091), increased Erk phosphorylation (PMID: 18632602, PMID: 29753091), increased cell proliferation and cell viability as compared to wild-type Map2k1, in two different cell lines (PMID: 29533785, PMID: 18632602), and also demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 K57N lung adenocarcinoma sensitive Selumetinib Preclinical Actionable In a preclinical study, selumetinib (AZD6244) inhibited phosphorylation of ERK in cells expressing MAP2K1 K57N and inhibited MAP2K1 K57N-dependent growth in cell culture (PMID: 18632602). 18632602