Home > Publications Database > AKT1E17K -mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363. > print

001     164093
005     20230915090549.0
024 7 _ |a 10.1111/nan.12780
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024 7 _ |a 0305-1846
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037 _ _ |a DZNE-2022-00756
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a John, Peter
|b 0
245 _ _ |a AKT1E17K -mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363.
260 _ _ |a Oxford [u.a.]
|c 2022
|b Wiley-Blackwell
336 7 _ |a article
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520 _ _ |a 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.
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650 _ 7 |a AKT1
|2 Other
650 _ 7 |a meningioma
|2 Other
650 _ 7 |a targeted therapy
|2 Other
650 _ 7 |a Enzyme Inhibitors
|2 NLM Chemicals
650 _ 7 |a Pyrimidines
|2 NLM Chemicals
650 _ 7 |a Pyrroles
|2 NLM Chemicals
650 _ 7 |a Proto-Oncogene Proteins c-akt
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 7 |a capivasertib
|0 WFR23M21IE
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Cell Proliferation: drug effects
|2 MeSH
650 _ 2 |a Enzyme Inhibitors: pharmacology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Meningeal Neoplasms: genetics
|2 MeSH
650 _ 2 |a Meningeal Neoplasms: pathology
|2 MeSH
650 _ 2 |a Meningioma: genetics
|2 MeSH
650 _ 2 |a Meningioma: pathology
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Proto-Oncogene Proteins c-akt: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Proto-Oncogene Proteins c-akt: genetics
|2 MeSH
650 _ 2 |a Pyrimidines: pharmacology
|2 MeSH
650 _ 2 |a Pyrroles: pharmacology
|2 MeSH
650 _ 2 |a Skull Base Neoplasms: genetics
|2 MeSH
650 _ 2 |a Skull Base Neoplasms: pathology
|2 MeSH
700 1 _ |a Waldt, Natalie
|b 1
700 1 _ |a Liebich, Josephine
|b 2
700 1 _ |a Kesseler, Christoph
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700 1 _ |a Schnabel, Stefan
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700 1 _ |a Angenstein, Frank
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700 1 _ |a Sandalcioglu, I Erol
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700 1 _ |a Scherlach, Cordula
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700 1 _ |a Sahm, Felix
|0 0000-0001-5441-1962
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700 1 _ |a Kirches, Elmar
|b 9
700 1 _ |a Mawrin, Christian
|0 0000-0002-6677-3124
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773 _ _ |a 10.1111/nan.12780
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856 4 _ |y OpenAccess
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