Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines.
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.
Witta
Samir E
SE
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
Gemmill
Robert M
RM
Hirsch
Fred R
FR
Coldren
Christopher D
CD
Hedman
Karla
K
Ravdel
Larisa
L
Helfrich
Barbara
B
Dziadziuszko
Rafal
R
Chan
Daniel C
DC
Sugita
Michio
M
Chan
Zeng
Z
Baron
Anna
A
Franklin
Wilbur
W
Drabkin
Harry A
HA
Girard
Luc
L
Gazdar
Adi F
AF
Minna
John D
JD
Bunn
Paul A
PA
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
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