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Proceedings of the National Academy of Sciences of the United States of America 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, TH, Tanaka, KE, Yun, CH, Zhang, X, Lee, SH, 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, KK, Meyerson, M
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue36
Pages14476-81
Date Published2012/09/04
ISSN0027-8424
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.

URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=22908275
DOI10.1073/pnas.1203201109
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22908275?dopt=Abstract