TAK-580 and Brain-Neoplasms

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

Activating mutations or structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549:BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA.. A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG-out" conformation of the kinase) was screened for drugs showing efficacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549:BRAF.. We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549:BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures.. MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas.

Topics: Animals; Astrocytoma; Blood-Brain Barrier; Brain Neoplasms; Child; Heterocyclic Compounds, 3-Ring; High-Throughput Screening Assays; Humans; Male; Mice; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Protein Multimerization; Proto-Oncogene Proteins B-raf; raf Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays