BACKGROUND: The 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).
METHODS: mTORC1 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.
RESULTS: Exposure 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.
CONCLUSIONS: These 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.