AKT1 E17K ‐mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363
| العنوان: | AKT1 E17K ‐mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363 |
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| المؤلفون: | Stefan Schnabel, Christian Mawrin, Felix Sahm, Natalie Waldt, Christoph Kesseler, Josephine Liebich, Peter John, C. Scherlach, Frank Angenstein, I. Erol Sandalcioglu, Elmar Kirches |
| المصدر: | Neuropathology & applied neurobiology 48(2), e12780 (2022). doi:10.1111/nan.12780 |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Histology, pathology [Meningeal Neoplasms], Cell, pharmacology [Enzyme Inhibitors], AKT1, Biology, medicine.disease_cause, meningioma, Pathology and Forensic Medicine, pharmacology [Pyrimidines], Meningioma, Mice, capivasertib, In vivo, Cell Line, Tumor, antagonists & inhibitors [Proto-Oncogene Proteins c-akt], pathology [Skull Base Neoplasms], Physiology (medical), otorhinolaryngologic diseases, medicine, Animals, Humans, Pyrroles, ddc:610, Enzyme Inhibitors, neoplasms, drug effects [Cell Proliferation], Mutation, genetics [Meningeal Neoplasms], Akt inhibitor AZD5363, Cell growth, genetics [Meningioma], targeted therapy, medicine.disease, nervous system diseases, Pyrimidines, medicine.anatomical_structure, Neurology, Cell culture, Cancer research, pharmacology [Pyrroles], genetics [Proto-Oncogene Proteins c-akt], genetics [Skull Base Neoplasms], Neurology (clinical), Proto-Oncogene Proteins c-akt, pathology [Meningioma] |
| الوصف: | Objectives 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. Materials and 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. Conclusion Our data suggest that AKT1E17K mutated meningiomas are a promising selective target for AZD5363. |
| تدمد: | 1365-2990 0305-1846 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8cca490852d8aecdd9a5e8a3886f1d3a https://doi.org/10.1111/nan.12780 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8cca490852d8aecdd9a5e8a3886f1d3a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 13652990 03051846 |
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