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RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition.


ABSTRACT: High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upon in vitro knockdown and accelerated tumor formation in a neuroblastoma zebrafish model coexpressing human RRM2 with MYCN. Forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition, while high RRM2 expression in human neuroblastomas correlates with high CHK1 activity. MYCN-driven zebrafish tumors with RRM2 co-overexpression exhibit differentially expressed DNA repair genes in keeping with enhanced ATR-CHK1 signaling activity. In vitro, RRM2 inhibition enhances intrinsic replication stress checkpoint addiction. Last, combinatorial RRM2-CHK1 inhibition acts synergistic in high-risk neuroblastoma cell lines and patient-derived xenograft models, illustrating the therapeutic potential.

SUBMITTER: Nunes C 

PROVIDER: S-EPMC9278860 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition.

Nunes Carolina C   Depestel Lisa L   Mus Liselot L   Keller Kaylee M KM   Delhaye Louis L   Louwagie Amber A   Rishfi Muhammad M   Whale Alex A   Kara Neesha N   Andrews Simon R SR   Dela Cruz Filemon F   You Daoqi D   Siddiquee Armaan A   Cologna Camila Takeno CT   De Craemer Sam S   Dolman Emmy E   Bartenhagen Christoph C   De Vloed Fanny F   Sanders Ellen E   Eggermont Aline A   Bekaert Sarah-Lee SL   Van Loocke Wouter W   Bek Jan Willem JW   Dewyn Givani G   Loontiens Siebe S   Van Isterdael Gert G   Decaesteker Bieke B   Tilleman Laurentijn L   Van Nieuwerburgh Filip F   Vermeirssen Vanessa V   Van Neste Christophe C   Ghesquiere Bart B   Goossens Steven S   Eyckerman Sven S   De Preter Katleen K   Fischer Matthias M   Houseley Jon J   Molenaar Jan J   De Wilde Bram B   Roberts Stephen S SS   Durinck Kaat K   Speleman Frank F  

Science advances 20220713 28


High-risk neuroblastoma, a pediatric tumor originating from the sympathetic nervous system, has a low mutation load but highly recurrent somatic DNA copy number variants. Previously, segmental gains and/or amplifications allowed identification of drivers for neuroblastoma development. Using this approach, combined with gene dosage impact on expression and survival, we identified ribonucleotide reductase subunit M2 (RRM2) as a candidate dependency factor further supported by growth inhibition upo  ...[more]

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