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

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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