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

Wang SE, Narasanna A, Perez-Torres M, Xiang B, Wu FY, Yang S, Carpenter G, Gazdar AF, Muthuswamy SK, Arteaga CL
Cancer Cell. 2006 10 (1): 25-38

PMID: 16843263 · DOI:10.1016/j.ccr.2006.05.023

HER2/Neu gene mutations have been identified in lung cancer. Expression of a HER2 mutant containing a G776(YVMA) 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. HER2(YVMA) transphosphorylated kinase-dead EGFR(K721R) and EGFR(WT) 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 HER2(YVMA). These data suggest that (1) HER2(YVMA) activates cellular substrates more potently than HER2(WT); and (2) cancer cells expressing this mutation remain sensitive to HER2-targeted therapies but insensitive to EGFR TKIs.

MeSH Terms (27)

Animals Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Apoptosis Cell Line, Tumor Cell Movement Cell Proliferation Drug Resistance, Neoplasm Epidermal Growth Factor ErbB Receptors Erlotinib Hydrochloride Female Gefitinib Humans Mice Mice, Nude Models, Biological Morpholines Mutation Phosphorylation Protein Kinase Inhibitors Quinazolines Receptor, ErbB-2 RNA, Small Interfering Transforming Growth Factor alpha Trastuzumab Xenograft Model Antitumor Assays

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