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@ARTICLE{John:164093,
      author       = {John, Peter and Waldt, Natalie and Liebich, Josephine and
                      Kesseler, Christoph and Schnabel, Stefan and Angenstein,
                      Frank and Sandalcioglu, I Erol and Scherlach, Cordula and
                      Sahm, Felix and Kirches, Elmar and Mawrin, Christian},
      title        = {{AKT}1{E}17{K} -mutated meningioma cell lines respond to
                      treatment with the {AKT} inhibitor {AZD}5363.},
      journal      = {Neuropathology $\&$ applied neurobiology},
      volume       = {48},
      number       = {2},
      issn         = {0305-1846},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {DZNE-2022-00756},
      pages        = {e12780},
      year         = {2022},
      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.},
      keywords     = {Animals / Cell Line, Tumor / Cell Proliferation: drug
                      effects / Enzyme Inhibitors: pharmacology / Humans /
                      Meningeal Neoplasms: genetics / Meningeal Neoplasms:
                      pathology / Meningioma: genetics / Meningioma: pathology /
                      Mice / Proto-Oncogene Proteins c-akt: antagonists $\&$
                      inhibitors / Proto-Oncogene Proteins c-akt: genetics /
                      Pyrimidines: pharmacology / Pyrroles: pharmacology / Skull
                      Base Neoplasms: genetics / Skull Base Neoplasms: pathology /
                      AKT1 (Other) / meningioma (Other) / targeted therapy (Other)
                      / Enzyme Inhibitors (NLM Chemicals) / Pyrimidines (NLM
                      Chemicals) / Pyrroles (NLM Chemicals) / Proto-Oncogene
                      Proteins c-akt (NLM Chemicals) / capivasertib (NLM
                      Chemicals)},
      cin          = {AG Angenstein},
      ddc          = {610},
      cid          = {I:(DE-2719)1310004},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34837233},
      doi          = {10.1111/nan.12780},
      url          = {https://pub.dzne.de/record/164093},
}