ErbB-3 expression is associated with E-cadherin and their coexpression restores response to gefitinib in non-small-cell lung cancer (NSCLC)

• Published in: Annals of oncology Vol. 20; no. 4; pp. 689 - 695
• Main Authors: Witta, S. E., Dziadziuszko, R., Yoshida, K., Hedman, K., Varella-Garcia, M., Bunn, P. A., Hirsch, F. R.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-04-2009; Oxford Publishing Limited (England)
• Subjects: Antineoplastic agents; Antineoplastic Agents - therapeutic use; Base Sequence; Biological and medical sciences; Blotting, Western; Cadherins - genetics; Cadherins - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cohort Studies; DNA Primers; E-cadherin; EGFR; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; ErbB3; Female; Gefitinib; Gene Expression Regulation, Neoplastic - drug effects; HDAC; Histone Deacetylase Inhibitors; Humans; Immunoprecipitation; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Male; Medical sciences; Middle Aged; NSCLC; Original; Pharmacology. Drug treatments; Pneumology; Quinazolines - therapeutic use; Receptor, ErbB-3 - genetics; Receptor, ErbB-3 - metabolism; TKI; Tumors of the respiratory system and mediastinum; TKI; NSCLC; E-cadherin; EGFR; ErbB3; HDAC; Antineoplastic agent; Histone deacetylase; Quinazoline derivatives; Lung cancer; Coexpression; non-small cell lung carcinoma; Epidermal growth factor receptor; Bronchus disease; Gefitinib; Protein-tyrosine kinase; E Cadherin; Lung disease; Enzyme; Tyrosine kinase inhibitor; Respiratory disease; Transferases; Cell adhesion molecule; Enzyme inhibitor; Malignant tumor; Gene expression; Cancer
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1093/annonc/mdn703

Background: Epidermal growth factor receptor (EGFR) inhibitors are effective in a subset of patients with non-small-cell lung cancer (NSCLC). We previously showed that E-cadherin expression associates with gefitinib activity. Here, we correlated the expressions of ErbB-3 and E-cadherin in NSCLC tumors and cell lines, their effect on response to gefitinib, and induction of both by the histone deacetylase (HDAC) inhibitors vorinostat and SNDX-275. Methods: Real-time RT-PCR was carried out on RNA isolated from 91 fresh-frozen NSCLC samples and from 21 NSCLC lines. Protein expression was evaluated with western blot and flow cytometry. Apoptosis was assessed using vibrant apoptosis assay. Results: Expressions of E-cadherin and ErbB-3 correlated significantly in primary tumors (r = 0.38, P < 0.001) and in cell lines (r = 0.88, P < 0.001). Cotransfection of ErbB-3 and E-cadherin in a gefitinib-resistant cell line showed enhanced apoptotic response to gefitinib. vorinostat and SNDX-275 induced ErbB-3 and E-cadherin in gefitinib-resistant cell lines. When gefitinib-resistant lines were treated with vorinostat and gefitinib, synergistic effects were detected in four of the five lines tested. Conclusion: ErbB-3 and E-cadherin are coexpressed and induced by HDAC inhibitors. For tumors with low ErbB-3 and E-cadherin expressions, the combination of HDAC and EGFR-tyrosine kinase inhibitors increased expression of both genes and produced more than additive apoptotic effect.