Abstract
Although malignant astrocytomas are a leading cause of cancer-related death in children, rational therapeutic strategies are lacking. We previously identified activating mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) (BRAF(T1799A) encoding BRAF(V600E)) in association with homozygous cyclin-dependent kinase inhibitor 2A (CDKN2A, encoding p14ARF and p16Ink4a) deletions in pediatric infiltrative astrocytomas. Here we report that BRAF(V600E) expression in neural progenitors (NPs) is insufficient for tumorigenesis and increases NP cellular differentiation as well as apoptosis. In contrast, astrocytomas are readily generated from NPs with additional Ink4a-Arf deletion. The BRAF(V600E) inhibitor PLX4720 significantly increased survival of mice after intracranial transplant of genetically relevant murine or human astrocytoma cells. Moreover, combination therapy using PLX4720 plus the Cyclin-dependent kinase (CDK) 4/6-specific inhibitor PD0332991 further extended survival relative to either monotherapy. Our findings indicate a rational therapeutic strategy for treating a subset of pediatric astrocytomas with BRAF(V600E) mutation and CDKN2A deficiency.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Astrocytoma / drug therapy*
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Astrocytoma / genetics
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Astrocytoma / pathology
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Blotting, Western
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cells, Cultured
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Child
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Cyclin-Dependent Kinase Inhibitor p16 / antagonists & inhibitors*
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Humans
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Immunohistochemistry
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Indoles / pharmacology
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Mice, Nude
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Mice, SCID
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Neural Stem Cells / cytology
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Neural Stem Cells / drug effects
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Neural Stem Cells / metabolism
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Phosphorylation / drug effects
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Piperazines / pharmacology
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Pyridines / pharmacology
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Sulfonamides / pharmacology
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Xenograft Model Antitumor Assays*
Substances
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Cyclin-Dependent Kinase Inhibitor p16
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Indoles
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PLX 4720
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Piperazines
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Pyridines
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Sulfonamides
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Braf protein, mouse
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Proto-Oncogene Proteins B-raf
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Extracellular Signal-Regulated MAP Kinases
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palbociclib