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 (AKT1E17K), 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 AKT1E17K 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 AKTE17K mutation significantly enhances meningioma cell
proliferation and colony size in vitro, resulting in significantly shortened survival times of
mice carrying convexity or skull base AKT1E17K 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 AKT1E17K mutated meningiomas are a promising
selective target for AZD5363.Projekt DEAL 202
