Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines

Samir E. Witta, Robert M. Gemmill, Fred R. Hirsch, Christopher D. Coldren, Karla Hedman, Larisa Ravdel, Barbara Helfrich, Rafal Dziadziuszko, Daniel C. Chan, Michio Sugita, Zeng Chan, Anna Baron, Wilbur Franklin, Harry A. Drabkin, Luc Girard, Adi F. Gazdar, John D. Minna, Paul A. Bunn

Research output: Contribution to journalArticle

408 Scopus citations

Abstract

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of non-small cell lung cancers (NSCLC). EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, produce 9% to 27% response rates in NSCLC patients. E-Cadherin, a calcium-dependent adhesion molecule, plays an important role in NSCLC prognosis and progression, and interacts with EGFR. The zinc finger transcriptional repressor, ZEB1, inhibits E-cadherin expression by recruiting histone deacetylases (HDAC). We identified a significant correlation between sensitivity to gefitinib and expression of E-cadherin, and ZEB1, suggesting their predictive value for responsiveness to EGFR-tyrosine kinase inhibitors. E-Cadherin transfection into a gefitinib-resistant line increased its sensitivity to gefitinib. Pretreating resistant cell lines with the HDAC inhibitor, MS-275, induced E-cadherin along with EGFR and led to a growth-inhibitory and apoptotic effect of gefitinib similar to that in gefitinib-sensitive NSCLC cell lines including those harboring EGFR mutations. Thus, combined HDAC inhibitor and gefitinib treatment represents a novel pharmacologic strategy for overcoming resistance to EGFR inhibitors in patients with lung cancer.

Original languageEnglish (US)
Pages (from-to)944-950
Number of pages7
JournalCancer research
Volume66
Issue number2
DOIs
StatePublished - Jan 15 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Witta, S. E., Gemmill, R. M., Hirsch, F. R., Coldren, C. D., Hedman, K., Ravdel, L., Helfrich, B., Dziadziuszko, R., Chan, D. C., Sugita, M., Chan, Z., Baron, A., Franklin, W., Drabkin, H. A., Girard, L., Gazdar, A. F., Minna, J. D., & Bunn, P. A. (2006). Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer research, 66(2), 944-950. https://doi.org/10.1158/0008-5472.CAN-05-1988