title: Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy.
abstract: Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 micromol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA. Christi.augustine@duke.edu
authors.forename: Christina K
authors.initials: CK
authors.lastname: Augustine
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Toshimitsu
authors.forename: Sin-Ho
authors.initials: SH
authors.lastname: Jung
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Zipfel
authors.forename: Jin S
authors.initials: JS
authors.lastname: Yoo
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Yoshimoto
authors.forename: M Angelica
authors.initials: MA
authors.lastname: Selim
authors.forename: James
authors.initials: J
authors.lastname: Burchette
authors.forename: Georgia M
authors.initials: GM
authors.lastname: Beasley
authors.forename: Nicole
authors.initials: N
authors.lastname: McMahon
authors.forename: James
authors.initials: J
authors.lastname: Padussis
authors.forename: Scott K
authors.initials: SK
authors.lastname: Pruitt
authors.forename: Francis
authors.initials: F
authors.lastname: Ali-Osman
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives; D009570:Nitriles / Q000494:pharmacology; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011923:Rats, Nude; D000077157:Sorafenib; D000077204:Temozolomide; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001557:Benzenesulfonates; D002070:Butadienes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; C113580:U 0126; D009536:Niacinamide; D003606:Dacarbazine; D000077157:Sorafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D008558:Melphalan; D000077204:Temozolomide