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ErbB-3 expression is associated with E-cadherin and their coexpression restores response to gefitinib in

S E Witta1, R Dziadziuszko, K Yoshida

  • 1Department of Medicine-Division of Medical Oncology, University of Colorado Health Sciences Center and University of Colorado Cancer Center, Aurora, CO 80010, USA. samir.witta@uchsc.edu

Annals of Oncology : Official Journal of the European Society for Medical Oncology
|January 20, 2009
PubMed
Abstract

Insights

Histone deacetylase (HDAC) inhibitors like vorinostat can increase ErbB-3 and E-cadherin expression in non-small-cell lung cancer (NSCLC). Combining HDAC inhibitors with EGFR-tyrosine kinase inhibitors shows synergistic effects, improving apoptosis in resistant NSCLC tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Epidermal growth factor receptor (EGFR) inhibitors benefit a subset of non-small-cell lung cancer (NSCLC) patients.
  • Previous studies linked E-cadherin expression to gefitinib activity.
  • This study investigates ErbB-3 and E-cadherin expression in NSCLC and their response to gefitinib.

Purpose of the Study:

  • To correlate ErbB-3 and E-cadherin expression in NSCLC tumors and cell lines.
  • To assess the impact of ErbB-3 and E-cadherin on gefitinib response.
  • To evaluate the induction of ErbB-3 and E-cadherin by histone deacetylase (HDAC) inhibitors vorinostat and SNDX-275.

Main Methods:

  • Real-time RT-PCR on 91 NSCLC samples and 21 cell lines.
  • Western blot and flow cytometry for protein expression analysis.
  • Vibrant apoptosis assay to assess cell death.

Main Results:

  • Significant correlation between E-cadherin and ErbB-3 expression in tumors (r=0.38) and cell lines (r=0.88).
  • Cotransfection of ErbB-3 and E-cadherin enhanced gefitinib-induced apoptosis in resistant cells.
  • Vorinostat and SNDX-275 induced ErbB-3 and E-cadherin in gefitinib-resistant NSCLC cell lines.
  • Synergistic effects observed when combining vorinostat and gefitinib in resistant cell lines.

Conclusions:

  • ErbB-3 and E-cadherin are coexpressed and can be induced by HDAC inhibitors in NSCLC.
  • Combining HDAC inhibitors with EGFR-tyrosine kinase inhibitors increases ErbB-3 and E-cadherin expression.
  • This combination therapy yields a greater than additive apoptotic effect in NSCLC tumors with low ErbB-3 and E-cadherin expression.

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