title: Sorafenib: complexities of Raf-dependent and Raf-independent signaling are now unveiled.
abstract: Hepatocellular carcinoma (HCC) is the most common primary cancer worldwide. The only current drug available for clinical treatment of HCC is sorafenib, which inhibits multiple signaling kinases including Raf family members, platelet-derived growth factor receptor, vascular endothelial growth factor receptors 1 and 2, c-Kit, and Fms-like tyrosine kinase 3. Many studies have revealed that the mechanism underlying the antitumor effect of sorafenib is complex. Because sorafenib inhibits C-Raf more potently than B-Raf, the therapeutic efficacy of sorafenib is strongly influenced by the relative expression and activity of B-Raf and C-Raf and the complex interactions between these factors. Moreover, Rafindependent signaling mechanisms have recently emerged as important pathways of sorafenib-induced cell death. Basic research studies have suggested that using sorafenib as part of a combination therapy may improve its effect, although this has yet to be confirmed by clinical evidence. Further studies of the functional mechanism of sorafenib are required to advance the development of targeted therapy for HCC. To aid future work on sorafenib, we here review the current literature pertaining to sorafenib signaling and its clinical efficacy in both monotherapy and combination therapy.
authors.affiliation: Department of Medical Technology, Niigata University Graduate School of Health Sciences, Asahimachi-dori, Niigata, Japan. yasunobu@med.niigata-u.ac.jp
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Manabu
authors.initials: M
authors.lastname: Fukumoto
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D000077157:Sorafenib; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048490:raf Kinases