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@ARTICLE{Merk:273911,
      author       = {Merk, Daniel J and Tsiami, Foteini and Hirsch, Sophie and
                      Walter, Bianca and Haeusser, Lara A and Maile, Jens D and
                      Stahl, Aaron and Jarboui, Mohamed A and Lechado-Terradas,
                      Anna and Klose, Franziska and Babaei, Sepideh and Admard,
                      Jakob and Casadei, Nicolas and Roggia, Cristiana and Spohn,
                      Michael and Schittenhelm, Jens and Singer, Stephan and
                      Schüller, Ulrich and Piccioni, Federica and Persky, Nicole
                      S and Claassen, Manfred and Tatagiba, Marcos and Kahle,
                      Philipp J and Root, David E and Templin, Markus and
                      Tabatabai, Ghazaleh},
      title        = {{F}unctional screening reveals genetic dependencies and
                      diverging cell cycle control in atypical teratoid rhabdoid
                      tumors.},
      journal      = {Genome biology},
      volume       = {25},
      number       = {1},
      issn         = {1465-6906},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2024-01385},
      pages        = {301},
      year         = {2024},
      abstract     = {Atypical teratoid rhabdoid tumors (ATRT) are incurable
                      high-grade pediatric brain tumors. Despite intensive
                      research efforts, the prognosis for ATRT patients under
                      currently established treatment protocols is poor. While
                      novel therapeutic strategies are urgently needed, the
                      generation of molecular-driven treatment concepts is a
                      challenge mainly due to the absence of actionable genetic
                      alterations.We here use a functional genomics approach to
                      identify genetic dependencies in ATRT, validate selected
                      hits using a functionally instructed small molecule drug
                      library, and observe preferential activity in ATRT cells
                      without subgroup-specific selectivity. CDK4/6 inhibitors are
                      among the most potent drugs and display anti-tumor efficacy
                      due to mutual exclusive dependency on CDK4 or CDK6.
                      Chemogenetic interactor screens reveal a broad spectrum of
                      G1 phase cell cycle regulators that differentially enable
                      cell cycle progression and modulate response to CDK4/6
                      inhibition in ATRT cells. In this regard, we find that the
                      ubiquitin ligase substrate receptor AMBRA1 acts as a
                      context-specific inhibitor of cell cycle progression by
                      regulating key components of mitosis including aurora
                      kinases.Our data provide a comprehensive resource of genetic
                      and chemical dependencies in ATRTs, which will inform
                      further preclinical evaluation of novel targeted therapies
                      for this tumor entity. Furthermore, this study reveals a
                      unique mechanism of cell cycle inhibition as the basis for
                      tumor suppressive functions of AMBRA1.},
      keywords     = {Humans / Rhabdoid Tumor: genetics / Rhabdoid Tumor: drug
                      therapy / Teratoma: genetics / Teratoma: pathology /
                      Teratoma: drug therapy / Teratoma: metabolism /
                      Cyclin-Dependent Kinase 6: metabolism / Cyclin-Dependent
                      Kinase 6: antagonists $\&$ inhibitors / Cyclin-Dependent
                      Kinase 6: genetics / Cell Line, Tumor / Cyclin-Dependent
                      Kinase 4: antagonists $\&$ inhibitors / Cyclin-Dependent
                      Kinase 4: metabolism / Cell Cycle Checkpoints: drug effects
                      / Antineoplastic Agents: pharmacology / Brain Neoplasms:
                      genetics / Brain Neoplasms: metabolism / Brain Neoplasms:
                      pathology / Brain Neoplasms: drug therapy / Cell Cycle /
                      Protein Kinase Inhibitors: pharmacology / AMBRA1 (Other) /
                      CDK4/6 inhibitors (Other) / CRISPR-Cas9 (Other) / Functional
                      screening (Other) / Genetic dependencies (Other) / Rhabdoid
                      tumors (Other) / Tumor suppressor (Other) / Cyclin-Dependent
                      Kinase 6 (NLM Chemicals) / Cyclin-Dependent Kinase 4 (NLM
                      Chemicals) / CDK6 protein, human (NLM Chemicals) /
                      Antineoplastic Agents (NLM Chemicals) / CDK4 protein, human
                      (NLM Chemicals) / Protein Kinase Inhibitors (NLM Chemicals)},
      cin          = {AG Kahle / AG Gasser},
      ddc          = {570},
      cid          = {I:(DE-2719)1210000-4 / I:(DE-2719)1210000},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39617889},
      pmc          = {pmc:PMC11610224},
      doi          = {10.1186/s13059-024-03438-w},
      url          = {https://pub.dzne.de/record/273911},
}