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

Abstract

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.

• Authors: S E Witta, R Dziadziuszko, K Yoshida, K Hedman, M Varella-Garcia, P A Bunn Jr, F R Hirsch
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 20 Issue 4 Pg. 689-95 (Apr 2009) ISSN: 1569-8041 [Electronic] England
• PMID: 19150934 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cadherins
• DNA Primers
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Quinazolines
• Receptor, ErbB-3
• Gefitinib

Topics

• Antineoplastic Agents (therapeutic use)
• Base Sequence
• Blotting, Western
• Cadherins (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Cohort Studies
• DNA Primers
• Enzyme Inhibitors (administration & dosage, pharmacology)
• Female
• Gefitinib
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors
• Humans
• Immunoprecipitation
• Lung Neoplasms (drug therapy, metabolism)
• Male
• Middle Aged
• Quinazolines (therapeutic use)
• Receptor, ErbB-3 (genetics, metabolism)