Inhibition of ATR prevents macropinocytosis driven retraction of neurites and opposes invasion in GBM

Abstract

Glioblastoma (GBM) is the most common and aggressive type of primary brain tumour and remains incurable despite decades of research. GBM are characterised by highly infiltrative growth patterns that contribute to the profound cognitive and neurological symptoms experienced by patients, and to inevitable recurrence following treatment. Novel treatments that reduce infiltration of the healthy brain have potential to ameliorate clinical symptoms and improve survival. Here, we report a novel role of the Ataxia telangiectasia and Rad 3 related kinase (ATR) in supporting the invasive properties of GBM cells through the regulation of macropinocytosis-driven internalisation of integrin adhesion receptors. We demonstrate that inhibition of ATR opposes GBM migration in vitro, and correspondingly reduces infiltrative behaviour in orthotopic mouse models. These results indicate that ATR inhibition, in addition to its use as a radiosensitiser, may be effective in reducing GBM infiltration and its associated symptoms.