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

Shizhen Emily Wang, Archana Narasanna, Marianela Perez-Torres, Bin Xiang, Frederick Y. Wu, Seungchan Yang, Graham Carpenter, Adi F. Gazdar, Senthil K. Muthuswamy, Carlos L. Arteaga

Research output: Contribution to journalArticle

334 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)25-38
Number of pages14
JournalCancer Cell
Volume10
Issue number1
DOIs
StatePublished - Jul 2006

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Protein-Tyrosine Kinases
Phosphotransferases
Phosphorylation
erbB-2 Genes
Mutation
Lung Neoplasms
Transducers
Exons
Apoptosis
Growth
Neoplasms
Therapeutics

Keywords

  • SIGNALING

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. / Wang, Shizhen Emily; Narasanna, Archana; Perez-Torres, Marianela; Xiang, Bin; Wu, Frederick Y.; Yang, Seungchan; Carpenter, Graham; Gazdar, Adi F.; Muthuswamy, Senthil K.; Arteaga, Carlos L.

In: Cancer Cell, Vol. 10, No. 1, 07.2006, p. 25-38.

Research output: Contribution to journalArticle

Wang, Shizhen Emily ; Narasanna, Archana ; Perez-Torres, Marianela ; Xiang, Bin ; Wu, Frederick Y. ; Yang, Seungchan ; Carpenter, Graham ; Gazdar, Adi F. ; Muthuswamy, Senthil K. ; Arteaga, Carlos L. / HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. In: Cancer Cell. 2006 ; Vol. 10, No. 1. pp. 25-38.
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AU - Wang, Shizhen Emily

AU - Narasanna, Archana

AU - Perez-Torres, Marianela

AU - Xiang, Bin

AU - Wu, Frederick Y.

AU - Yang, Seungchan

AU - Carpenter, Graham

AU - Gazdar, Adi F.

AU - Muthuswamy, Senthil K.

AU - Arteaga, Carlos L.

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AB - 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.

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