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

Item Type:Article
Title:Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2
Creators Name:Greulich, H. and Kaplan, B. and Mertins, P. and Chen, T.H. and Tanaka, K.E. and Yun, C.H. and Zhang, X. and Lee, S.H. and Cho, J. and Ambrogio, L. and Liao, R. and Imielinski, M. and Banerji, S. and Berger, A.H. and Lawrence, M.S. and Zhang, J. and Pho, N.H. and Walker, S.R. and Winckler, W. and Getz, G. and Frank, D. and Hahn, W.C. and Eck, M.J. and Mani, D.R. and Jaffe, J.D. and Carr, S.A. and Wong, K.K. and Meyerson, M.
Abstract: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.
Keywords:HER2, Breast Cancer, Bladder Cancer, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:109
Number:36
Page Range:14476-14481
Date:4 September 2012
Official Publication:https://doi.org/10.1073/pnas.1203201109
PubMed:View item in PubMed

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