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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1203201109

Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2.

Publication TypeJournal Article
Year of Publication2012
AuthorsGreulich, H, Kaplan, B, Mertins, P, Chen, T-H, Tanaka, KE, Yun, C-H, Zhang, X, Lee, S-H, Cho, J, Ambrogio, L, Liao, R, Imielinski, M, Banerji, S, Berger, AH, Lawrence, MS, Zhang, J, Pho, NH, Walker, SR, Winckler, W, Getz, G, Frank, D, Hahn, WC, Eck, MJ, Mani, DR, Jaffe, JD, Carr, SA, Wong, K-K, Meyerson, M
JournalProc Natl Acad Sci U S A
Date Published2012 Sep 04
KeywordsAdenocarcinoma, Alleles, Animals, Cell Movement, Cloning, Molecular, Dimerization, DNA Primers, Immunoblotting, Lung Neoplasms, Mice, Mutation, NIH 3T3 Cells, Phosphorylation, Protein Structure, Tertiary, Receptor, ErbB-2, Retroviridae, Tandem Mass Spectrometry

We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity. Five of these genes failed to score in transformation assays; however, novel recurring extracellular domain mutations of the receptor tyrosine kinase gene ERBB2 were potently oncogenic. These ERBB2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C-terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation. These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins, impacting cell motility. Survival of Ba/F3 cells transformed to IL-3 independence by the ERBB2 extracellular domain mutants was abrogated by treatment with small-molecule inhibitors of ERBB2, raising the possibility that patients harboring such mutations could benefit from ERBB2-directed therapy.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22908275
PubMed Central IDPMC3437859
Grant ListP20 CA090578 / CA / NCI NIH HHS / United States
P20CA90578 / CA / NCI NIH HHS / United States
R01CA116020 / CA / NCI NIH HHS / United States
R01CA109038 / CA / NCI NIH HHS / United States
R01 CA109038 / CA / NCI NIH HHS / United States
R01 CA116020 / CA / NCI NIH HHS / United States