HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors

Wang, S. E., Narasanna, A., Perez-Torres, M., Xiang, B., Wu, F. Y., Yang, S., Carpenter, G., Gazdar, A. F., Muthuswamy, S. K., Arteaga, C. L. (2006) HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell, 10 (1). pp. 25-38. ISSN 15356108

URL: https://www.ncbi.nlm.nih.gov/pubmed/16843263
DOI: 10.1016/j.ccr.2006.05.023

Abstract

HER2/Neu gene mutations have been identified in lung cancer. Expression of a HER2 mutant containing a G776YVMA insertion in exon 20 was more potent than wild-type HER2 in associating with and activating signal transducers, phosphorylating EGFR, and inducing survival, invasiveness, and tumorigenicity. HER2YVMA transphosphorylated kinase-dead EGFRK721R and EGFRWT in the presence of EGFR tyrosine kinase inhibitors (TKIs). Knockdown of mutant HER2 in H1781 lung cancer cells increased apoptosis and restored sensitivity to EGFR TKIs. The HER2 inhibitors lapatinib, trastuzumab, and CI-1033 inhibited growth of H1781 cells and cells expressing exogenous HER2YVMA. These data suggest that (1) HER2YVMA activates cellular substrates more potently than HER2WT; and (2) cancer cells expressing this mutation remain sensitive to HER2-targeted therapies but insensitive to EGFR TKIs. © 2006 Elsevier Inc. All rights reserved.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > HER2
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
diseases & disorders > cancer > cancer types > lung cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation > transduction
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation > transduction

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Muthuswamy lab
Depositing User: CSHL Librarian
Date: 2006
Date Deposited: 06 Dec 2011 19:25
Last Modified: 27 Apr 2018 19:53
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22923

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