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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1117255109

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

Publication TypeJournal Article
Year of Publication2012
AuthorsHuillard, E, Hashizume, R, Phillips, JJ, Griveau, A, Ihrie, RA, Aoki, Y, Nicolaides, T, Perry, A, Waldman, T, McMahon, M, Weiss, WA, Petritsch, C, C James, D, Rowitch, DH
JournalProc Natl Acad Sci U S A
Volume109
Issue22
Pages8710-5
Date Published2012 May 29
ISSN1091-6490
KeywordsAnimals, 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
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.

URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=22586120
DOI10.1073/pnas.1117255109
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22586120?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22586120
PubMed Central IDPMC3365162
Grant ListR01 NS040511 / NS / NINDS NIH HHS / United States
K08 NS063456 / NS / NINDS NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
1R01CA164746 / CA / NCI NIH HHS / United States
K08 NS065268 / NS / NINDS NIH HHS / United States
R01 CA131261 / CA / NCI NIH HHS / United States
R01 NS080619 / NS / NINDS NIH HHS / United States
R01 NS057727 / NS / NINDS NIH HHS / United States
R01 CA159467 / CA / NCI NIH HHS / United States
R01 CA164746 / CA / NCI NIH HHS / United States
R01CA131261 / CA / NCI NIH HHS / United States
5K08NS063456 / NS / NINDS NIH HHS / United States
K08NS065268 / NS / NINDS NIH HHS / United States
P50 CA097257 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
2R01NS057727-05 / NS / NINDS NIH HHS / United States
CA097257 / CA / NCI NIH HHS / United States
R01CA159467 / CA / NCI NIH HHS / United States