title: Fibroblast growth factor receptors as therapeutic targets in human melanoma: synergism with BRAF inhibition.
abstract: Cutaneous melanoma is a tumor with rising incidence and a very poor prognosis at the disseminated stage. Melanomas are characterized by frequent mutations in BRAF and also by overexpression of fibroblast growth factor 2 (FGF2), offering opportunities for therapeutic intervention. We investigated inhibition of FGF signaling and its combination with dacarbazine or BRAF inhibitors as an antitumor strategy in melanoma. The majority of melanoma cell lines displayed overexpression of FGF2 but also FGF5 and FGF18 together with different isoforms of FGF receptors (FGFRs) 1-4. Blockade of FGF signals with dominant-negative receptor constructs (dnFGFR1, 3, or 4) or small-molecule inhibitors (SU5402 and PD166866) reduced melanoma cell proliferation, colony formation, as well as anchorage-independent growth, and increased apoptosis. DnFGFR constructs also significantly inhibited tumor growth in vivo. Combination of FGF inhibitors with dacarbazine showed additive or antagonistic effects, whereas synergistic drug interaction was observed when combining FGFR inhibition with the multikinase/BRAF inhibitor sorafenib or the V600E mutant-specific BRAF inhibitor RG7204. In conclusion, FGFR inhibition has antitumor effects against melanoma cells in vitro and in vivo. Combination with BRAF inhibition offers a potential for synergistic antimelanoma effects and represents a promising therapeutic strategy against advanced melanoma.
authors.affiliation: Department of Medicine I, Comprehensive Cancer Center, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Metzner
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bedeir
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Held
authors.forename: Barbara
authors.initials: B
authors.lastname: Peter-Vörösmarty
authors.forename: Sara
authors.initials: S
authors.lastname: Ghassemi
authors.forename: Christine
authors.initials: C
authors.lastname: Heinzle
authors.forename: Sabine
authors.initials: S
authors.lastname: Spiegl-Kreinecker
authors.forename: Brigitte
authors.initials: B
authors.lastname: Marian
authors.forename: Klaus
authors.initials: K
authors.lastname: Holzmann
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.forename: Michael
authors.initials: M
authors.lastname: Micksche
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D001557:Benzenesulfonates / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage; D004354:Drug Screening Assays, Antitumor; D005799:Genes, Dominant; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008544:Melanocytes / Q000166:cytology; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000473:pathology / Q000628:therapy*; D000077157:Sorafenib; D013449:Sulfonamides / Q000008:administration & dosage; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D011725:Pyridines; D017468:Receptors, Fibroblast Growth Factor; D013449:Sulfonamides; D000077484:Vemurafenib; D009536:Niacinamide; D003606:Dacarbazine; D000077157:Sorafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf