TY  - JOUR
AU  - Merk, Daniel J
AU  - Tsiami, Foteini
AU  - Hirsch, Sophie
AU  - Walter, Bianca
AU  - Haeusser, Lara A
AU  - Maile, Jens D
AU  - Stahl, Aaron
AU  - Jarboui, Mohamed A
AU  - Lechado-Terradas, Anna
AU  - Klose, Franziska
AU  - Babaei, Sepideh
AU  - Admard, Jakob
AU  - Casadei, Nicolas
AU  - Roggia, Cristiana
AU  - Spohn, Michael
AU  - Schittenhelm, Jens
AU  - Singer, Stephan
AU  - Schüller, Ulrich
AU  - Piccioni, Federica
AU  - Persky, Nicole S
AU  - Claassen, Manfred
AU  - Tatagiba, Marcos
AU  - Kahle, Philipp J
AU  - Root, David E
AU  - Templin, Markus
AU  - Tabatabai, Ghazaleh
TI  - Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors.
JO  - Genome biology
VL  - 25
IS  - 1
SN  - 1465-6906
CY  - London
PB  - BioMed Central
M1  - DZNE-2024-01385
SP  - 301
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Rhabdoid Tumor: genetics
KW  - Rhabdoid Tumor: drug therapy
KW  - Teratoma: genetics
KW  - Teratoma: pathology
KW  - Teratoma: drug therapy
KW  - Teratoma: metabolism
KW  - Cyclin-Dependent Kinase 6: metabolism
KW  - Cyclin-Dependent Kinase 6: antagonists & inhibitors
KW  - Cyclin-Dependent Kinase 6: genetics
KW  - Cell Line, Tumor
KW  - Cyclin-Dependent Kinase 4: antagonists & inhibitors
KW  - Cyclin-Dependent Kinase 4: metabolism
KW  - Cell Cycle Checkpoints: drug effects
KW  - Antineoplastic Agents: pharmacology
KW  - Brain Neoplasms: genetics
KW  - Brain Neoplasms: metabolism
KW  - Brain Neoplasms: pathology
KW  - Brain Neoplasms: drug therapy
KW  - Cell Cycle
KW  - Protein Kinase Inhibitors: pharmacology
KW  - AMBRA1 (Other)
KW  - CDK4/6 inhibitors (Other)
KW  - CRISPR-Cas9 (Other)
KW  - Functional screening (Other)
KW  - Genetic dependencies (Other)
KW  - Rhabdoid tumors (Other)
KW  - Tumor suppressor (Other)
KW  - Cyclin-Dependent Kinase 6 (NLM Chemicals)
KW  - Cyclin-Dependent Kinase 4 (NLM Chemicals)
KW  - CDK6 protein, human (NLM Chemicals)
KW  - Antineoplastic Agents (NLM Chemicals)
KW  - CDK4 protein, human (NLM Chemicals)
KW  - Protein Kinase Inhibitors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39617889
C2  - pmc:PMC11610224
DO  - DOI:10.1186/s13059-024-03438-w
UR  - https://pub.dzne.de/record/273911
ER  -