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


CONCLUSIONS
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.
Witta
S E
SE
Department 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
Dziadziuszko
R
R
Yoshida
K
K
Hedman
K
K
Varella-Garcia
M
M
Bunn
P A
PA
Hirsch
F R
FR
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D015331:Cohort Studies; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000627:therapeutic use*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D015820:Cadherins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011799:Quinazolines; D020893:Receptor, ErbB-3; D000077156:Gefitinib