Journal Article

DZNE-2024-01385

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors.

Merk, D. J. ; Tsiami, F. ; Hirsch, S. ; Walter, B. ; Haeusser, L. A. ; Maile, J. D. ; Stahl, A. ; Jarboui, M. A. ; Lechado-Terradas, A.DZNE* ; Klose, F. ; Babaei, S. ; Admard, J. ; Casadei, N. ; Roggia, C. ; Spohn, M. ; Schittenhelm, J. ; Singer, S. ; Schüller, U. ; Piccioni, F. ; Persky, N. S. ; Claassen, M. ; Tatagiba, M. ; Kahle, P. J.DZNE* ; Root, D. E. ; Templin, M. ; Tabatabai, G.

2024
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s13059-024-03438-w

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.

Keyword(s): Humans (MeSH) ; Rhabdoid Tumor: genetics (MeSH) ; Rhabdoid Tumor: drug therapy (MeSH) ; Teratoma: genetics (MeSH) ; Teratoma: pathology (MeSH) ; Teratoma: drug therapy (MeSH) ; Teratoma: metabolism (MeSH) ; Cyclin-Dependent Kinase 6: metabolism (MeSH) ; Cyclin-Dependent Kinase 6: antagonists & inhibitors (MeSH) ; Cyclin-Dependent Kinase 6: genetics (MeSH) ; Cell Line, Tumor (MeSH) ; Cyclin-Dependent Kinase 4: antagonists & inhibitors (MeSH) ; Cyclin-Dependent Kinase 4: metabolism (MeSH) ; Cell Cycle Checkpoints: drug effects (MeSH) ; Antineoplastic Agents: pharmacology (MeSH) ; Brain Neoplasms: genetics (MeSH) ; Brain Neoplasms: metabolism (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Brain Neoplasms: drug therapy (MeSH) ; Cell Cycle (MeSH) ; Protein Kinase Inhibitors: pharmacology (MeSH) ; AMBRA1 ; CDK4/6 inhibitors ; CRISPR-Cas9 ; Functional screening ; Genetic dependencies ; Rhabdoid tumors ; Tumor suppressor ; Cyclin-Dependent Kinase 6 ; Cyclin-Dependent Kinase 4 ; CDK6 protein, human ; Antineoplastic Agents ; CDK4 protein, human ; Protein Kinase Inhibitors

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Contributing Institute(s):

1. Functional Neurogenetics (AG Kahle)
2. Parkinson Genetics (AG Gasser)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2024

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