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.
journal_name
Proc Natl Acad Sci U S Aauthors
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 DHdoi
10.1073/pnas.1117255109subject
Has Abstractpub_date
2012-05-29 00:00:00pages
8710-5issue
22eissn
0027-8424issn
1091-6490pii
1117255109journal_volume
109pub_type
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