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[Cancer Research 66, 944-950, January 15, 2006]
© 2006 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Restoring E-Cadherin Expression Increases Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cell Lines

Samir E. Witta1, Robert M. Gemmill1, Fred R. Hirsch1,2, Christopher D. Coldren1, Karla Hedman1, Larisa Ravdel1, Barbara Helfrich1, Rafal Dziadziuszko1,4, Daniel C. Chan1, Michio Sugita2, Zeng Chan3, Anna Baron3, Wilbur Franklin2, Harry A. Drabkin1, Luc Girard5, Adi F. Gazdar5, John D. Minna5 and Paul A. Bunn, Jr.1

Departments of 1 Medicine/Medical Oncology, 2 Pathology, and 3 Preventive Medicine and Biometrics, University of Colorado Health Sciences Center and University of Colorado Cancer Center, Aurora, Colorado; 4 Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; and 5 Hamon Center for Therapeutic Oncology Research, Dallas, Texas

Requests for reprints: Samir E. Witta, Department of Medicine/Medical Oncology, University of Colorado Health Sciences Center, Campus Box 8117, P.O. Box 6511, Aurora, CO 80045. Phone: 303-724-3876; Fax: 303-724-3889; E-mail: Samir.Witta{at}uchsc.edu.

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. (Cancer Res 2006; 66(2); 944-50)




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