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Novel MEK1 Mutation Identified by Mutational Analysis of Epidermal Growth Factor Receptor Signaling Pathway Genes in Lung Adenocarcinoma

¹ Human Oncology and Pathogenesis Program, ² Department of Pathology, ³ Thoracic Service, Department of Surgery, and ⁴ Department of Medicine, Memorial Sloan-Kettering Cancer Center; ⁵ Department of Medicine, Weill Medical College of Cornell University, New York, New York; ⁶ Genome Sequencing Center, Washington University School of Medicine, St. Louis, Missouri; ⁷ Max Planck Institute for Neurological Research; and ⁸ Department for Internal Medicine, University of Cologne, Cologne, Germany

Requests for reprints: William Pao, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 417 East 68th Street, ZRC 602, New York, NY 10065. Phone: 646-888-2642; Fax: 646-888-2595; E-mail: paow{at}mskcc.org.

Key Words: MEK1 • MAP2K1 • mutation • lung cancer • MEK inhibitor • AZD6244

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. [Cancer Res 2008;68(14):5524–8]

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