title: EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib.
abstract: Sorafenib is currently the medical treatment of reference for hepatocellular carcinoma (HCC), but it is not known whether sorafenib is equally active in all HCC. Here, our aim was to explore intrinsic differences in the response of HCC cells to sorafenib, to identify potential mechanisms leading to primary resistance to this treatment. We analyzed a panel of six human HCC cell lines and compared the activity of the main oncogenic kinase cascades, their clonogenic potential, proliferation and apoptosis upon exposure to sorafenib. We report that HCC cells present important differences in their response to sorafenib, and that some cell lines are more resistant to the actions of sorafenib than others. We identify the activated epidermal growth factor receptor (EGFR) as a parameter that promotes the resistance of HCC cells to sorafenib. In resistant cells, the efficacy of sorafenib was increased when EGFR was inhibited, as was demonstrated using two chemical inhibitors (erlotinib or gefitinib), a monoclonal antibody directed against EGFR (cetuximab), and RNA interference directed against EGFR. A combination of EGFR inhibitors and sorafenib affords a better control over HCC proliferation, most likely through an improved blockade of the RAF kinases. Our findings therefore confirm the importance of RAF kinases as therapeutic targets in HCC, and identify EGFR as a determinant of the sensitivity of HCC cells to sorafenib. Our findings bear possible implications for the improvement of the efficacy of sorafenib in HCC, and might be useful for the identification of predictive biomarkers in this context.
authors.affiliation: Inserm U1088, Faculté de Médecine, Université de Picardie Jules Verne, Amiens, France.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Ezzoukhry
authors.forename: Christophe
authors.initials: C
authors.lastname: Louandre
authors.forename: Eric
authors.initials: E
authors.lastname: Trécherel
authors.forename: Corinne
authors.initials: C
authors.lastname: Godin
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dupont
authors.forename: Momar
authors.initials: M
authors.lastname: Diouf
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Barbare
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Mazière
authors.forename: Antoine
authors.initials: A
authors.lastname: Galmiche
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use*; D034622:RNA Interference; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D066246:ErbB Receptors