The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells

Jenna Kahn, Thomas J. Hayman, Muhammad Jamal, Barbara H. Rath, Tamalee Kramp, Kevin Camphausen, Philip J. Tofilon

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

BackgroundThe mammalian target of rapamycin (mTOR) has been suggested as a target for radiosensitization. Given that radiotherapy is a primary treatment modality for glioblastoma (GBM) and that mTOR is often dysregulated in GBM, the goal of this study was to determine the effects of AZD2014, a dual mTORC1/2 inhibitor, on the radiosensitivity of GBM stem-like cells (GSCs).MethodsmTORC1 and mTORC2 activities were defined by immunoblot analysis. The effects of this mTOR inhibitor on the in vitro radiosensitivity of GSCs were determined using a clonogenic assay. DNA double strand breaks were evaluated according to γH2AX foci. Orthotopic xenografts initiated from GSCs were used to define the in vivo response to AZD2014 and radiation.ResultsExposure of GSCs to AZD2014 resulted in the inhibition of mTORC1 and 2 activities. Based on clonogenic survival analysis, addition of AZD2014 to culture media 1 hour before irradiation enhanced the radiosensitivity of CD133+ and CD15+ GSC cell lines. Whereas AZD2014 treatment had no effect on the initial level of γH2AX foci, the dispersal of radiation-induced γH2AX foci was significantly delayed. Finally, the combination of AZD2014 and radiation delivered to mice bearing GSC-initiated orthotopic xenografts significantly prolonged survival as compared with the individual treatments.ConclusionsThese data indicate that AZD2014 enhances the radiosensitivity of GSCs both in vitro and under orthotopic in vivo conditions and suggest that this effect involves an inhibition of DNA repair. Moreover, these results suggest that this dual mTORC1/2 inhibitor may be a radiosensitizer applicable to GBM therapy.

Original languageEnglish (US)
Pages (from-to)29-37
Number of pages9
JournalNeuro-Oncology
Volume16
Issue number1
DOIs
StatePublished - Jan 2014
Externally publishedYes

Keywords

  • AZD2014
  • Radiation
  • glioblastoma
  • mTOR
  • orthotopic xenograft
  • tumor stem cell

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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