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Neuro Oncol. 2017 Jun 1;19(6):774-785. doi: 10.1093/neuonc/now261.

A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas.

Author information

1
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
3
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
4
Center for Molecular Oncologic Pathology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
5
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
6
Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
7
Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
8
Program in Molecular Pharmacology, Department of Medicine, and Center for Mechanism Based Therapeutics Memorial Sloan Kettering Cancer Center, New York, USA.
9
Division of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts, USA.
10
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
12
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
13
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.
14
Departments of Neurosurgery and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
15
Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Background:

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.

Methods:

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.

Results:

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.

Conclusion:

MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas.

KEYWORDS:

MLN2480; RAF dimers; pediatric low-grade astrocytoma

PMID:
28082416
PMCID:
PMC5464455
DOI:
10.1093/neuonc/now261
[Indexed for MEDLINE]
Free PMC Article

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