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

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 2; pp. 944 - 950
• Main Authors: Witta, Samir E, Gemmill, Robert M, Hirsch, Fred R, Coldren, Christopher D, Hedman, Karla, Ravdel, Larisa, Helfrich, Barbara, Dziadziuszko, Rafal, Chan, Daniel C, Sugita, Michio, Chan, Zeng, Baron, Anna, Franklin, Wilbur, Drabkin, Harry A, Girard, Luc, Gazdar, Adi F, Minna, John D, Bunn, Jr, Paul A
• Format: Journal Article
• Language: English
• Published: United States 15-01-2006
• Subjects: Antineoplastic Agents - pharmacology; Biomarkers, Tumor - analysis; Cadherins - biosynthesis; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Disease Progression; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Homeodomain Proteins - biosynthesis; Humans; Lung Neoplasms - pathology; Predictive Value of Tests; Prognosis; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - physiology; Transcription Factors - biosynthesis; Transfection; Zinc Finger E-box-Binding Homeobox 1
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-1988

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.