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

Emmanuelle Huillard, Rintaro Hashizume, Joanna J. Phillips, Amélie Griveau, Rebecca A. Ihrie, Yasuyuki Aoki, Theodore Nicolaides, Arie Perry, Todd Waldman, Martin McMahon, William A. Weiss, Claudia Petritsch, C. David James*, David H. Rowitch

*Corresponding author for this work

Research output: Contribution to journalArticle

54 Scopus citations

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) (BRAFT1799A encoding BRAFV600E) in association with homozygous cyclin-dependent kinase inhibitor 2A (CDKN2A, encoding p14ARF and p16Ink4a) deletions in pediatric infiltrative astrocytomas. Here we report that BRAFV600Eexpression 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 BRAFV600E 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 BRAFV600E mutation and CDKN2A deficiency.

Original languageEnglish (US)
Pages (from-to)8710-8715
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number22
DOIs
StatePublished - May 29 2012

Keywords

  • Glioma
  • Protein kinase
  • Tumor suppressor

ASJC Scopus subject areas

  • General

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    Huillard, E., Hashizume, R., Phillips, J. J., Griveau, A., Ihrie, R. A., Aoki, Y., Nicolaides, T., Perry, A., Waldman, T., McMahon, M., Weiss, W. A., Petritsch, C., James, C. D., & Rowitch, D. H. (2012). Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proceedings of the National Academy of Sciences of the United States of America, 109(22), 8710-8715. https://doi.org/10.1073/pnas.1117255109