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000273911 037__ $$aDZNE-2024-01385
000273911 041__ $$aEnglish
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000273911 1001_ $$00000-0003-2935-6919$$aMerk, Daniel J$$b0
000273911 245__ $$aFunctional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors.
000273911 260__ $$aLondon$$bBioMed Central$$c2024
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000273911 520__ $$aAtypical 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.
000273911 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000273911 650_7 $$2Other$$aAMBRA1
000273911 650_7 $$2Other$$aCDK4/6 inhibitors
000273911 650_7 $$2Other$$aCRISPR-Cas9
000273911 650_7 $$2Other$$aFunctional screening
000273911 650_7 $$2Other$$aGenetic dependencies
000273911 650_7 $$2Other$$aRhabdoid tumors
000273911 650_7 $$2Other$$aTumor suppressor
000273911 650_7 $$0EC 2.7.11.22$$2NLM Chemicals$$aCyclin-Dependent Kinase 6
000273911 650_7 $$0EC 2.7.11.22$$2NLM Chemicals$$aCyclin-Dependent Kinase 4
000273911 650_7 $$0EC 2.7.11.22$$2NLM Chemicals$$aCDK6 protein, human
000273911 650_7 $$2NLM Chemicals$$aAntineoplastic Agents
000273911 650_7 $$0EC 2.7.11.22$$2NLM Chemicals$$aCDK4 protein, human
000273911 650_7 $$2NLM Chemicals$$aProtein Kinase Inhibitors
000273911 650_2 $$2MeSH$$aHumans
000273911 650_2 $$2MeSH$$aRhabdoid Tumor: genetics
000273911 650_2 $$2MeSH$$aRhabdoid Tumor: drug therapy
000273911 650_2 $$2MeSH$$aTeratoma: genetics
000273911 650_2 $$2MeSH$$aTeratoma: pathology
000273911 650_2 $$2MeSH$$aTeratoma: drug therapy
000273911 650_2 $$2MeSH$$aTeratoma: metabolism
000273911 650_2 $$2MeSH$$aCyclin-Dependent Kinase 6: metabolism
000273911 650_2 $$2MeSH$$aCyclin-Dependent Kinase 6: antagonists & inhibitors
000273911 650_2 $$2MeSH$$aCyclin-Dependent Kinase 6: genetics
000273911 650_2 $$2MeSH$$aCell Line, Tumor
000273911 650_2 $$2MeSH$$aCyclin-Dependent Kinase 4: antagonists & inhibitors
000273911 650_2 $$2MeSH$$aCyclin-Dependent Kinase 4: metabolism
000273911 650_2 $$2MeSH$$aCell Cycle Checkpoints: drug effects
000273911 650_2 $$2MeSH$$aAntineoplastic Agents: pharmacology
000273911 650_2 $$2MeSH$$aBrain Neoplasms: genetics
000273911 650_2 $$2MeSH$$aBrain Neoplasms: metabolism
000273911 650_2 $$2MeSH$$aBrain Neoplasms: pathology
000273911 650_2 $$2MeSH$$aBrain Neoplasms: drug therapy
000273911 650_2 $$2MeSH$$aCell Cycle
000273911 650_2 $$2MeSH$$aProtein Kinase Inhibitors: pharmacology
000273911 7001_ $$00009-0001-6070-0434$$aTsiami, Foteini$$b1
000273911 7001_ $$aHirsch, Sophie$$b2
000273911 7001_ $$00000-0001-9734-4843$$aWalter, Bianca$$b3
000273911 7001_ $$00000-0002-3288-4280$$aHaeusser, Lara A$$b4
000273911 7001_ $$aMaile, Jens D$$b5
000273911 7001_ $$00000-0003-3616-9564$$aStahl, Aaron$$b6
000273911 7001_ $$00000-0002-5203-235X$$aJarboui, Mohamed A$$b7
000273911 7001_ $$0P:(DE-2719)9002265$$aLechado-Terradas, Anna$$b8$$udzne
000273911 7001_ $$aKlose, Franziska$$b9
000273911 7001_ $$00000-0002-5957-6907$$aBabaei, Sepideh$$b10
000273911 7001_ $$00000-0003-0466-582X$$aAdmard, Jakob$$b11
000273911 7001_ $$00000-0003-2209-0580$$aCasadei, Nicolas$$b12
000273911 7001_ $$aRoggia, Cristiana$$b13
000273911 7001_ $$aSpohn, Michael$$b14
000273911 7001_ $$00000-0002-9168-6209$$aSchittenhelm, Jens$$b15
000273911 7001_ $$aSinger, Stephan$$b16
000273911 7001_ $$0P:(DE-2719)9000979$$aSchüller, Ulrich$$b17
000273911 7001_ $$00000-0003-1210-3210$$aPiccioni, Federica$$b18
000273911 7001_ $$00000-0002-9948-2761$$aPersky, Nicole S$$b19
000273911 7001_ $$00000-0002-4583-9083$$aClaassen, Manfred$$b20
000273911 7001_ $$00000-0002-1627-9937$$aTatagiba, Marcos$$b21
000273911 7001_ $$0P:(DE-2719)2810803$$aKahle, Philipp J$$b22
000273911 7001_ $$00000-0001-5122-861X$$aRoot, David E$$b23
000273911 7001_ $$00000-0002-6569-6489$$aTemplin, Markus$$b24
000273911 7001_ $$00000-0002-3542-8782$$aTabatabai, Ghazaleh$$b25
000273911 773__ $$0PERI:(DE-600)2040529-7$$a10.1186/s13059-024-03438-w$$gVol. 25, no. 1, p. 301$$n1$$p301$$tGenome biology$$v25$$x1465-6906$$y2024
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