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Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2.
|Publication Type||Journal Article|
|Authors||Greulich, 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 D. R., Jaffe JD, Carr SA, Wong KK, 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.|
|Year of Publication||2012|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Date Published (YYYY/MM/DD)||2012/09/04|