Document Detail

Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells.
MedLine Citation:
PMID:  22414764     Owner:  NLM     Status:  MEDLINE    
BACKGROUND & AIMS: Sorafenib is the standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, primary and acquired resistance is observed in patients. We examined whether gefitinib, which inhibits both epidermal growth factor receptor (EGFR) and HER-3 phosphorylation, could improve HCC cell response to sorafenib.
METHODS: Sorafenib and gefitinib were tested in HCC tumor xenografts and in sorafenib-sensitive and sorafenib-resistant HCC cell lines. Biomarkers relevant to the HER system were analyzed by Western blotting and ELISA. RNA interference was used to downregulate the HER system. Amphiregulin concentrations were measured by ELISA in sera from patients under sorafenib treatment.
RESULTS: Sorafenib combined with gefitinib significantly inhibited tumor growth in mice and reduced cell viability in vitro compared to single agents. In cell lines cultured in 10% serum or treated with EGF, sorafenib alone inhibited phospho-STAT3 while it maintained or even increased phospho-ERK and/or phospho-AKT. The paradoxical effects of sorafenib were prevented by gefitinib or by downregulation of EGFR and HER-3 expression. In cells with acquired resistance to sorafenib, aberrant activation of EGFR/HER-3 receptors as well as overexpression of several EGFR ligands were observed. These enhanced autocrine/paracrine loops led to the constitutive activation of ERK and AKT and conferred increased sensitivity to gefitinib. Increased serum concentrations of amphiregulin were observed in 10 out of 14 patients under sorafenib treatment compared to baselines.
CONCLUSIONS: Signaling pathways controlled by EGFR and HER-3 restrict sorafenib effects both in naive and sorafenib-resistant HCC cells. Consequently, gefitinib cooperates with sorafenib to increase antiproliferative response and to prevent resistance.
Marie-José Blivet-Van Eggelpoël; Hamza Chettouh; Laetitia Fartoux; Lynda Aoudjehane; Véronique Barbu; Colette Rey; Sabrina Priam; Chantal Housset; Olivier Rosmorduc; Christèle Desbois-Mouthon
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-10
Journal Detail:
Title:  Journal of hepatology     Volume:  57     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-19     Completed Date:  2012-11-05     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  England    
Other Details:
Languages:  eng     Pagination:  108-15     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
UPMC Univ Paris 06, UMR_S 938, F-75012 Paris, France.
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MeSH Terms
Aged, 80 and over
Antineoplastic Agents / pharmacology*,  therapeutic use
Benzenesulfonates / pharmacology*,  therapeutic use
Carcinoma, Hepatocellular / drug therapy*,  metabolism,  pathology
Cell Division / drug effects,  physiology
Drug Resistance, Neoplasm / physiology
Glycoproteins / metabolism
Hep G2 Cells
Intercellular Signaling Peptides and Proteins / metabolism
Liver Neoplasms, Experimental / drug therapy*,  metabolism,  pathology
MAP Kinase Signaling System / drug effects,  physiology
Mice, Nude
Middle Aged
Pyridines / pharmacology*,  therapeutic use
Quinazolines / pharmacology
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  metabolism*
Receptor, erbB-3 / metabolism*
Tumor Markers, Biological / metabolism
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/Antineoplastic Agents; 0/Benzenesulfonates; 0/Glycoproteins; 0/Intercellular Signaling Peptides and Proteins; 0/Pyridines; 0/Quinazolines; 0/Tumor Markers, Biological; 0/sorafenib; 117147-70-3/amphiregulin; EC, Epidermal Growth Factor; EC, erbB-3; S65743JHBS/gefitinib

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