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

Proc Natl Acad Sci U S A
Authors
Keywords
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
Proc Natl Acad Sci U S A
Volume
109
Issue
36
Pages
14476-81
Date Published
2012 Sep 04
ISSN
1091-6490
URL
DOI
10.1073/pnas.1203201109
PubMed ID
22908275
PubMed Central ID
PMC3437859
Links
Grant list
P20 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