title: A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas.
abstract: 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.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Alberta
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pilarz
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Calligaris
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Chadwick
authors.affiliation: Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Shakti H
authors.initials: SH
authors.lastname: Ramkissoon
authors.affiliation: Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Ramkissoon
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Veronica Matia
authors.initials: VM
authors.lastname: Garcia
authors.affiliation: Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Mazzola
authors.affiliation: Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Liliana
authors.initials: L
authors.lastname: Goumnerova
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kane
authors.affiliation: Program in Molecular Pharmacology, Department of Medicine, and Center for Mechanism Based Therapeutics Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Division of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.affiliation: Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Program in Molecular Pharmacology, Department of Medicine, and Center for Mechanism Based Therapeutics Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Departments of Neurosurgery and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nathalie Y
authors.initials: NY
authors.lastname: Agar
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Buhrlage
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Segal
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Stiles
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002648:Child; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; C568616:BRAF-KIAA1549 fusion protein, human; C000626518:tovorafenib; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles
keywords: MLN2480; RAF dimers; pediatric low-grade astrocytoma