TAK-580 and Melanoma

Targeted inhibition of RAF and MEK by molecularly targeted agents has been employed as a strategy to block aberrant mitogen-activated protein kinase (MAPK) signaling in melanoma. While the use of BRAF and MEK inhibitors, either as a single agent or in combination, improved efficacy in BRAF-mutant melanoma, initial responses are often followed by relapse due to acquired resistance. Moreover, some BRAF inhibitors are associated with paradoxical activation of the MAPK pathway, causing the development of secondary malignancies. The use of panRAF inhibitors, i.e., those that target all isoforms of RAF, may overcome paradoxical activation and resistance. The purpose of this study was to perform a quantitative assessment and evaluation of the influence of efflux mechanisms at the blood-brain barrier (BBB), in particular, Abcb1/P-glycoprotein (P-gp) and Abcg2/breast cancer resistance protein (Bcrp), on the brain distribution of three panRAF inhibitors: CCT196969 [1-(3-(

Topics: Animals; Brain; Brain Neoplasms; Cell Line, Tumor; Dogs; Dose-Response Relationship, Drug; Female; Heterocyclic Compounds, 3-Ring; Humans; Madin Darby Canine Kidney Cells; Male; Melanoma; Mice; Mice, Knockout; Phenylurea Compounds; Phosphatidylethanolamine Binding Protein; Pyrazines; Pyrimidines