| Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. | |
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MedLine Citation:
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PMID: 22414764 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 down-regulation of EGFR and HER-3 expressions. 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 the 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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-3-10 |
Journal Detail:
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Title: Journal of hepatology Volume: - ISSN: 0168-8278 ISO Abbreviation: - Publication Date: 2012 Mar |
Date Detail:
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Created Date: 2012-3-14 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8503886 Medline TA: J Hepatol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012. Published by Elsevier B.V. |
Affiliation:
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UPMC Univ Paris 06, UMR_S 938, F-75012, Paris, France; INSERM UMR_S 938, Centre de Recherche Saint-Antoine, F-75012, Paris, France. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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