title: The broad-spectrum receptor tyrosine kinase inhibitor dovitinib suppresses growth of BRAF-mutant melanoma cells in combination with other signaling pathway inhibitors.
abstract: BRAF inhibitors have revolutionized treatment of mutant BRAF metastatic melanomas. However, resistance develops rapidly following BRAF inhibitor treatment. We have found that BRAF-mutant melanoma cell lines are more sensitive than wild-type BRAF cells to the small molecule tyrosine kinase inhibitor dovitinib. Sensitivity is associated with inhibition of a series of known dovitinib targets. Dovitinib in combination with several agents inhibits growth more effectively than either agent alone. These combinations inhibit BRAF-mutant melanoma and colorectal carcinoma cell lines, including cell lines with intrinsic or selected BRAF inhibitor resistance. Hence, combinations of dovitinib with second agents are potentially effective therapies for BRAF-mutant melanomas, regardless of their sensitivity to BRAF inhibitors.
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Casey G
authors: CG
authors: Langdon
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Matthew A
authors: MA
authors: Held
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.|Breast Medical Oncology Group, Yale University School of Medicine, New Haven, CT, USA.
authors: James T
authors: JT
authors: Platt
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Katrina
authors: K
authors: Meeth
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Pinar
authors: P
authors: Iyidogan
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Ramanaiah
authors: R
authors: Mamillapalli
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Andrew B
authors: AB
authors: Koo
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Michael
authors: M
authors: Klein
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: Zongzhi
authors: Z
authors: Liu
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.|Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors: Marcus W
authors: MW
authors: Bosenberg
authors: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors: David F
authors: DF
authors: Stern
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms; D054852:Small Molecule Libraries / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib; D000096142:Cutaneous Malignant Melanoma
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; C517975:AZD 6244; D001562:Benzimidazoles; D007211:Indoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D054852:Small Molecule Libraries; D013449:Sulfonamides; D000077484:Vemurafenib
keywords: MEK inhibitor; combination therapy; dovitinib; mutant BRAF; vemurafenib resistance