Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma

Tina Dasgupta*, Aleksandra K. Olow, Xiaodong Yang, Rintaro Hashizume, Theodore P. Nicolaides, Maxwell Tom, Yasuyuki Aoki, Mitchel S. Berger, William A. Weiss, Lukas J.A. Stalpers, Michael Prados, C. David James, Sabine Mueller, Daphne A. Haas-Kogan

*Corresponding author for this work

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10–20 % of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.

Original languageEnglish (US)
Pages (from-to)385-393
Number of pages9
JournalJournal of Neuro-Oncology
Volume126
Issue number3
DOIs
StatePublished - Feb 1 2016

Keywords

  • BRAF V600E
  • High-grade gliomas
  • Radiotherapy
  • Targeted inhibitors

ASJC Scopus subject areas

  • Clinical Neurology
  • Cancer Research
  • Oncology
  • Neurology

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  • Cite this

    Dasgupta, T., Olow, A. K., Yang, X., Hashizume, R., Nicolaides, T. P., Tom, M., Aoki, Y., Berger, M. S., Weiss, W. A., Stalpers, L. J. A., Prados, M., David James, C., Mueller, S., & Haas-Kogan, D. A. (2016). Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. Journal of Neuro-Oncology, 126(3), 385-393. https://doi.org/10.1007/s11060-015-1939-2