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

Autor: Nunes C; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Depestel L; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Mus L; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Keller KM; Princess Maxima Center, Utrecht, Netherlands., Delhaye L; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; VIB-UGent Center for Medical Biotechnology, Ghent University, Ghent, Belgium., Louwagie A; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Rishfi M; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Whale A; Epigenetics Programme, Babraham Institute, Cambridge, UK., Kara N; Epigenetics Programme, Babraham Institute, Cambridge, UK., Andrews SR; Epigenetics Programme, Babraham Institute, Cambridge, UK., Dela Cruz F; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., You D; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Siddiquee A; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Cologna CT; Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.; Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium., De Craemer S; Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.; Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium., Dolman E; Princess Maxima Center, Utrecht, Netherlands., Bartenhagen C; Center for Molecular Medicine Cologne, Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany., De Vloed F; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Sanders E; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Eggermont A; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Bekaert SL; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium., Van Loocke W; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Bek JW; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Dewyn G; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Loontiens S; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Van Isterdael G; VIB Flow Core Facility, Ghent University, Ghent, Belgium., Decaesteker B; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Tilleman L; NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium., Van Nieuwerburgh F; NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium., Vermeirssen V; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium., Van Neste C; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Ghesquiere B; Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.; Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium., Goossens S; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; Department of Diagnostic Sciences, Ghent University, Ghent, Belgium., Eyckerman S; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; VIB-UGent Center for Medical Biotechnology, Ghent University, Ghent, Belgium., De Preter K; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Fischer M; Center for Molecular Medicine Cologne, Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.; Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Cologne, Germany., Houseley J; Epigenetics Programme, Babraham Institute, Cambridge, UK., Molenaar J; Princess Maxima Center, Utrecht, Netherlands., De Wilde B; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Roberts SS; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Durinck K; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Speleman F; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2022 Jul 15; Vol. 8 (28), pp. eabn1382. Date of Electronic Publication: 2022 Jul 13.
DOI: 10.1126/sciadv.abn1382
Abstrakt: 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.
Databáze: MEDLINE