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

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.

SUBMITTER: Greulich H

PROVIDER: S-EPMC3437859 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Greulich Heidi H Kaplan Bethany B Mertins Philipp P Chen Tzu-Hsiu TH Tanaka Kumiko E KE Yun Cai-Hong CH Zhang Xiaohong X Lee Se-Hoon SH Cho Jeonghee J Ambrogio Lauren L Liao Rachel R Imielinski Marcin M Banerji Shantanu S Berger Alice H AH Lawrence Michael S MS Zhang Jinghui J Pho Nam H NH Walker Sarah R SR Winckler Wendy W Getz Gad G Frank David D Hahn William C WC Eck Michael J MJ Mani D R DR Jaffe Jacob D JD Carr Steven A SA Wong Kwok-Kin KK Meyerson Matthew M

Proceedings of the National Academy of Sciences of the United States of America 20120820 36

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 intermolecu ...[more]

PMID: 22908275

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

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

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