AKT1(E17K)-mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363

Aims Meningiomas are the most frequent primary brain tumours. Recently, knowledge about the molecular drivers underlying aggressive meningiomas has been expanded. A hotspot mutation in the AKT1 gene (AKT1(E17K)), which is found in meningiomas at the convexity and especially at the skull base, has been associated with earlier tumour recurrence. Methods Here, we analysed the effects of the AKT1(E17K) mutation and treatment response to the Akt inhibitor AZD5363 in transgenic meningioma cell clones and mouse xenografts modelling convexity or skull base meningiomas. Results We show that the AKT(E17K) mutation significantly enhances meningioma cell proliferation and colony size in vitro, resulting in significantly shortened survival times of mice carrying convexity or skull base AKT1(E17K) xenografts. Treatment of mutant cells or xenografts (150 mg/kg/d) with AZD5363 revealed a significant decrease in cell proliferation and colony size and a prolongation of mouse survival. Western blots revealed activation of AKT1 kinase (phosphorylation at Ser273 and Thr308) by the E17K mutation in human meningioma samples and in our in vitro and in vivo models. Conclusions Our data suggest that AKT1(E17K) mutated meningiomas are a promising selective target for AZD5363.