Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy.

Huillard E, Hashizume R, Phillips JJ, Griveau A, Ihrie RA, Aoki Y, Nicolaides T, Perry A, Waldman T, McMahon M, Weiss WA, Petritsch C, James CD, Rowitch DH
Proc Natl Acad Sci U S A. 2012 109 (22): 8710-5

PMID: 22586120 · PMCID: PMC3365162 · DOI:10.1073/pnas.1117255109

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.

MeSH Terms (27)

Animals Apoptosis Astrocytoma Blotting, Western Cell Differentiation Cell Line, Tumor Cell Proliferation Cells, Cultured Child Cyclin-Dependent Kinase Inhibitor p16 Extracellular Signal-Regulated MAP Kinases Female Humans Immunohistochemistry Indoles Mice Mice, Inbred BALB C Mice, Knockout Mice, Nude Mice, SCID Neural Stem Cells Phosphorylation Piperazines Proto-Oncogene Proteins B-raf Pyridines Sulfonamides Xenograft Model Antitumor Assays

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