RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition-Reference-Cited by-同舟云学术

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

Published:2022-07-15 Issue:28 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Nunes Carolina¹²^ORCID,Depestel Lisa¹²^ORCID,Mus Liselot¹²^ORCID,Keller Kaylee M.³,Delhaye Louis¹²⁴^ORCID,Louwagie Amber¹²^ORCID,Rishfi Muhammad¹²^ORCID,Whale Alex⁵^ORCID,Kara Neesha⁵^ORCID,Andrews Simon R.⁵^ORCID,Dela Cruz Filemon⁶^ORCID,You Daoqi⁶,Siddiquee Armaan⁶,Cologna Camila Takeno⁷⁸^ORCID,De Craemer Sam⁷⁸^ORCID,Dolman Emmy³^ORCID,Bartenhagen Christoph⁹¹⁰,De Vloed Fanny¹²^ORCID,Sanders Ellen¹²,Eggermont Aline¹²,Bekaert Sarah-Lee¹,Van Loocke Wouter¹²^ORCID,Bek Jan Willem¹²^ORCID,Dewyn Givani¹²,Loontiens Siebe¹²^ORCID,Van Isterdael Gert¹¹^ORCID,Decaesteker Bieke¹²^ORCID,Tilleman Laurentijn¹²^ORCID,Van Nieuwerburgh Filip¹²^ORCID,Vermeirssen Vanessa¹²¹³^ORCID,Van Neste Christophe¹²^ORCID,Ghesquiere Bart⁷⁸^ORCID,Goossens Steven¹²¹⁴,Eyckerman Sven¹²⁴^ORCID,De Preter Katleen¹²^ORCID,Fischer Matthias⁹¹⁰^ORCID,Houseley Jon⁵^ORCID,Molenaar Jan³^ORCID,De Wilde Bram¹²^ORCID,Roberts Stephen S.⁶^ORCID,Durinck Kaat¹²^ORCID,Speleman Frank¹²

Affiliation:

1. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.

2. Cancer Research Institute Ghent (CRIG), Ghent, Belgium.

3. Princess Maxima Center, Utrecht, Netherlands.

4. VIB-UGent Center for Medical Biotechnology, Ghent University, Ghent, Belgium.

5. Epigenetics Programme, Babraham Institute, Cambridge, UK.

6. Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

7. Metabolomics Expertise Center, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.

8. Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium.

9. Center for Molecular Medicine Cologne, Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.

10. Department of Experimental Pediatric Oncology, University Children’s Hospital of Cologne, Cologne, Germany.

11. VIB Flow Core Facility, Ghent University, Ghent, Belgium.

12. NXTGNT, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.

13. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.

14. Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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