Journal Article

DZNE-2022-00756

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png AKT1E17K -mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363.

John, P. ; Waldt, N. ; Liebich, J. ; Kesseler, C. ; Schnabel, S. ; Angenstein, F.DZNE* ; Sandalcioglu, I. E. ; Scherlach, C. ; Sahm, F. ; Kirches, E. ; Mawrin, C.

2022
Wiley-Blackwell Oxford [u.a.]

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Please use a persistent id in citations: doi:10.1111/nan.12780

Abstract: 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.

Keyword(s): Animals (MeSH) ; Cell Line, Tumor (MeSH) ; Cell Proliferation: drug effects (MeSH) ; Enzyme Inhibitors: pharmacology (MeSH) ; Humans (MeSH) ; Meningeal Neoplasms: genetics (MeSH) ; Meningeal Neoplasms: pathology (MeSH) ; Meningioma: genetics (MeSH) ; Meningioma: pathology (MeSH) ; Mice (MeSH) ; Proto-Oncogene Proteins c-akt: antagonists & inhibitors (MeSH) ; Proto-Oncogene Proteins c-akt: genetics (MeSH) ; Pyrimidines: pharmacology (MeSH) ; Pyrroles: pharmacology (MeSH) ; Skull Base Neoplasms: genetics (MeSH) ; Skull Base Neoplasms: pathology (MeSH) ; AKT1 ; meningioma ; targeted therapy ; Enzyme Inhibitors ; Pyrimidines ; Pyrroles ; Proto-Oncogene Proteins c-akt ; capivasertib

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Contributing Institute(s):

1. Functional Neuroimaging (AG Angenstein)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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