title: Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines.
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.
authors.affiliation: Department of Medicine/Medical Oncology, University of Colorado Health Sciences Center and University of Colorado Cancer Center, Campus Box 8117, PO Box 6511, Aurora, CO 80045, USA. Samir.Witta@uchsc.edu
authors.forename: Samir E
authors.initials: SE
authors.lastname: Witta
authors.forename: Robert M
authors.initials: RM
authors.lastname: Gemmill
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Coldren
authors.forename: Karla
authors.initials: K
authors.lastname: Hedman
authors.forename: Larisa
authors.initials: L
authors.lastname: Ravdel
authors.forename: Barbara
authors.initials: B
authors.lastname: Helfrich
authors.forename: Rafal
authors.initials: R
authors.lastname: Dziadziuszko
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Chan
authors.forename: Michio
authors.initials: M
authors.lastname: Sugita
authors.forename: Zeng
authors.initials: Z
authors.lastname: Chan
authors.forename: Anna
authors.initials: A
authors.lastname: Baron
authors.forename: Wilbur
authors.initials: W
authors.lastname: Franklin
authors.forename: Harry A
authors.initials: HA
authors.lastname: Drabkin
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis; D015820:Cadherins / Q000096:biosynthesis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077156:Gefitinib; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D011237:Predictive Value of Tests; D011379:Prognosis; D011799:Quinazolines / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis; D014162:Transfection; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; D011799:Quinazolines; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D066246:ErbB Receptors; D000077156:Gefitinib