TY  - JOUR
AU  - John, Peter
AU  - Waldt, Natalie
AU  - Liebich, Josephine
AU  - Kesseler, Christoph
AU  - Schnabel, Stefan
AU  - Angenstein, Frank
AU  - Sandalcioglu, I Erol
AU  - Scherlach, Cordula
AU  - Sahm, Felix
AU  - Kirches, Elmar
AU  - Mawrin, Christian
TI  - AKT1E17K -mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363.
JO  - Neuropathology & applied neurobiology
VL  - 48
IS  - 2
SN  - 0305-1846
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - DZNE-2022-00756
SP  - e12780
PY  - 2022
AB  - 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.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.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.Our data suggest that AKT1E17K mutated meningiomas are a promising selective target for AZD5363.
KW  - Animals
KW  - Cell Line, Tumor
KW  - Cell Proliferation: drug effects
KW  - Enzyme Inhibitors: pharmacology
KW  - Humans
KW  - Meningeal Neoplasms: genetics
KW  - Meningeal Neoplasms: pathology
KW  - Meningioma: genetics
KW  - Meningioma: pathology
KW  - Mice
KW  - Proto-Oncogene Proteins c-akt: antagonists & inhibitors
KW  - Proto-Oncogene Proteins c-akt: genetics
KW  - Pyrimidines: pharmacology
KW  - Pyrroles: pharmacology
KW  - Skull Base Neoplasms: genetics
KW  - Skull Base Neoplasms: pathology
KW  - AKT1 (Other)
KW  - meningioma (Other)
KW  - targeted therapy (Other)
KW  - Enzyme Inhibitors (NLM Chemicals)
KW  - Pyrimidines (NLM Chemicals)
KW  - Pyrroles (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-akt (NLM Chemicals)
KW  - capivasertib (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34837233
DO  - DOI:10.1111/nan.12780
UR  - https://pub.dzne.de/record/164093
ER  -