title: Sorafenib and DE605, a novel c-Met inhibitor, synergistically suppress hepatocellular carcinoma.
abstract: Sorafenib, an oral multikinase inhibitor of Raf, VEGF and PDGF receptor signaling is approved for advanced hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. Aberrant mesenchymal-epithelial transition factor (c-Met) activation is associated with a variety of human malignancies and therefore represents a target for therapy. In this study, we investigated a novel c-Met inhibitor, DE605, together with sorafenib in hepatocellular carcinoma cells in vitro and in vivo. DE605 and sorafenib synergistically induced apoptosis in hepatocellular carcinoma cells. Mechanistically, DE605 activated the FGFR3/Erk pathway, which in turn was inhibited by sorafenib, resulting in synergism. Finally, DE605 and sorafenib significantly inhibited growth of PLC/PRF/5 hepatocellular carcinoma tumor xenografts in athymic nude mice. Importantly, no obvious weight loss (toxicity) was detected. Thus in combination, DE605 and sorafenib target complementary anti-apoptotic pathways and synergistically suppress HCC, providing the rationale for clinical studies with this novel combination.
authors.affiliation: Department of General Surgery, Wuxi People's Hospital, Wuxi, China.|Nanjing Medical University, Nanjing, China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Nanjing Medical University, Nanjing, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Feng
authors.affiliation: Department of General Surgery, Wuxi People's Hospital, Wuxi, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Nanjing Medical University, Nanjing, China.
authors.forename: Zengyao
authors.initials: Z
authors.lastname: Li
authors.affiliation: Nanjing Medical University, Nanjing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, Wuxi People's Hospital, Wuxi, China.
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Dou
authors.affiliation: Department of General Surgery, Wuxi People's Hospital, Wuxi, China.|Nanjing Medical University, Nanjing, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000008:administration & dosage*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D000077157:Sorafenib; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C580772:(4-(4-(6-amino-5-(benzo(d)oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanone; D000631:Aminopyridines; D001583:Benzoxazoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib; D019859:Proto-Oncogene Proteins c-met
keywords: c-Met inhibitor; combination; hepatocellular carcinoma; sorafenib