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Annals of Oncology Advance Access originally published online on January 15, 2009
Annals of Oncology 2009 20(4):689-695; doi:10.1093/annonc/mdn703
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

lung cancer

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

S. E. Witta1,*, R. Dziadziuszko3, K. Yoshida1, K. Hedman1, M. Varella-Garcia1, P. A. Bunn, Jr1 and F. R. Hirsch1,2

1 Department of Medicine–Division of Medical Oncology
2 Department of Pathology, University of Colorado Health Sciences Center and University of Colorado Cancer Center, Aurora, USA
3 Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland

* Correspondence to: Dr S. E. Witta, University of Colorado Cancer Center, Room L18-8402F, 12801 E.17th Avenue, Aurora, CO 80010, USA. Tel: +1-303-870-3293; Fax: +1-303-267-4448; E-mail: samir.witta{at}uchsc.edu

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.

Key words: E-cadherin, EGFR, ErbB3, HDAC, NSCLC, TKI

Received for publication August 13, 2008. Revision received October 6, 2008. Accepted for publication October 8, 2008.


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