Home > Publications Database > Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors. > print

001     273911
005     20241208000106.0
024 7 _ |a 10.1186/s13059-024-03438-w
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024 7 _ |a pmid:39617889
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024 7 _ |a 1465-6906
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024 7 _ |a 1465-6914
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024 7 _ |a 1474-7596
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024 7 _ |a 1474-760X
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024 7 _ |a altmetric:171531562
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037 _ _ |a DZNE-2024-01385
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Merk, Daniel J
|0 0000-0003-2935-6919
|b 0
245 _ _ |a Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors.
260 _ _ |a London
|c 2024
|b BioMed Central
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
650 _ 7 |a AMBRA1
|2 Other
650 _ 7 |a CDK4/6 inhibitors
|2 Other
650 _ 7 |a CRISPR-Cas9
|2 Other
650 _ 7 |a Functional screening
|2 Other
650 _ 7 |a Genetic dependencies
|2 Other
650 _ 7 |a Rhabdoid tumors
|2 Other
650 _ 7 |a Tumor suppressor
|2 Other
650 _ 7 |a Cyclin-Dependent Kinase 6
|0 EC 2.7.11.22
|2 NLM Chemicals
650 _ 7 |a Cyclin-Dependent Kinase 4
|0 EC 2.7.11.22
|2 NLM Chemicals
650 _ 7 |a CDK6 protein, human
|0 EC 2.7.11.22
|2 NLM Chemicals
650 _ 7 |a Antineoplastic Agents
|2 NLM Chemicals
650 _ 7 |a CDK4 protein, human
|0 EC 2.7.11.22
|2 NLM Chemicals
650 _ 7 |a Protein Kinase Inhibitors
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Rhabdoid Tumor: genetics
|2 MeSH
650 _ 2 |a Rhabdoid Tumor: drug therapy
|2 MeSH
650 _ 2 |a Teratoma: genetics
|2 MeSH
650 _ 2 |a Teratoma: pathology
|2 MeSH
650 _ 2 |a Teratoma: drug therapy
|2 MeSH
650 _ 2 |a Teratoma: metabolism
|2 MeSH
650 _ 2 |a Cyclin-Dependent Kinase 6: metabolism
|2 MeSH
650 _ 2 |a Cyclin-Dependent Kinase 6: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Cyclin-Dependent Kinase 6: genetics
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Cyclin-Dependent Kinase 4: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Cyclin-Dependent Kinase 4: metabolism
|2 MeSH
650 _ 2 |a Cell Cycle Checkpoints: drug effects
|2 MeSH
650 _ 2 |a Antineoplastic Agents: pharmacology
|2 MeSH
650 _ 2 |a Brain Neoplasms: genetics
|2 MeSH
650 _ 2 |a Brain Neoplasms: metabolism
|2 MeSH
650 _ 2 |a Brain Neoplasms: pathology
|2 MeSH
650 _ 2 |a Brain Neoplasms: drug therapy
|2 MeSH
650 _ 2 |a Cell Cycle
|2 MeSH
650 _ 2 |a Protein Kinase Inhibitors: pharmacology
|2 MeSH
700 1 _ |a Tsiami, Foteini
|0 0009-0001-6070-0434
|b 1
700 1 _ |a Hirsch, Sophie
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700 1 _ |a Walter, Bianca
|0 0000-0001-9734-4843
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700 1 _ |a Haeusser, Lara A
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700 1 _ |a Maile, Jens D
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700 1 _ |a Stahl, Aaron
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700 1 _ |a Jarboui, Mohamed A
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700 1 _ |a Lechado-Terradas, Anna
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700 1 _ |a Klose, Franziska
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700 1 _ |a Babaei, Sepideh
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700 1 _ |a Admard, Jakob
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700 1 _ |a Casadei, Nicolas
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700 1 _ |a Roggia, Cristiana
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700 1 _ |a Spohn, Michael
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700 1 _ |a Schittenhelm, Jens
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700 1 _ |a Singer, Stephan
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700 1 _ |a Schüller, Ulrich
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700 1 _ |a Piccioni, Federica
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700 1 _ |a Persky, Nicole S
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700 1 _ |a Kahle, Philipp J
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700 1 _ |a Root, David E
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700 1 _ |a Templin, Markus
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700 1 _ |a Tabatabai, Ghazaleh
|0 0000-0002-3542-8782
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773 _ _ |a 10.1186/s13059-024-03438-w
|g Vol. 25, no. 1, p. 301
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|t Genome biology
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|x 1465-6906
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