Nunes, Carolina ORCID: 0000-0002-8564-6171, Depestel, Lisa ORCID: 0000-0001-5690-3258, Mus, Liselot, Keller, Kaylee M. ORCID: 0000-0002-3130-7465, Delhaye, Louis ORCID: 0000-0001-8876-7385, Louwagie, Amber ORCID: 0000-0003-1808-6749, Rishfi, Muhammad ORCID: 0000-0002-6386-4485, Whale, Alex, Kara, Neesha, Andrews, Simon R., Dela Cruz, Filemon, You, Daoqi, Siddiquee, Armaan, Cologna, Camila Takeno, De Craemer, Sam, Dolman, Emmy, Bartenhagen, Christoph, De Vloed, Fanny, Sanders, Ellen, Eggermont, Aline, Bekaert, Sarah-Lee ORCID: 0000-0002-4769-3460, Van Loocke, Wouter, Bek, Jan Willem ORCID: 0000-0003-1337-1970, Dewyn, Givani, Loontiens, Siebe ORCID: 0000-0002-4602-4580, Van Isterdael, Gert ORCID: 0000-0001-6626-1316, Decaesteker, Bieke, Tilleman, Laurentijn ORCID: 0000-0001-7584-1179, Van Nieuwerburgh, Filip ORCID: 0000-0001-8815-5485, Vermeirssen, Vanessa, Van Neste, Christophe, Ghesquiere, Bart ORCID: 0000-0003-1547-1705, Goossens, Steven, Eyckerman, Sven, De Preter, Katleen, Fischer, Matthias, Houseley, Jon, Molenaar, Jan, De Wilde, Bram ORCID: 0000-0003-0213-1322, Roberts, Stephen S., Durinck, Kaat ORCID: 0000-0003-1762-5739 and Speleman, Frank (2022). RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition. Sci. Adv., 8 (28). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 2375-2548

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Nunes, CarolinaUNSPECIFIEDorcid.org/0000-0002-8564-6171UNSPECIFIED
Depestel, LisaUNSPECIFIEDorcid.org/0000-0001-5690-3258UNSPECIFIED
Mus, LiselotUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keller, Kaylee M.UNSPECIFIEDorcid.org/0000-0002-3130-7465UNSPECIFIED
Delhaye, LouisUNSPECIFIEDorcid.org/0000-0001-8876-7385UNSPECIFIED
Louwagie, AmberUNSPECIFIEDorcid.org/0000-0003-1808-6749UNSPECIFIED
Rishfi, MuhammadUNSPECIFIEDorcid.org/0000-0002-6386-4485UNSPECIFIED
Whale, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kara, NeeshaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrews, Simon R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dela Cruz, FilemonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
You, DaoqiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siddiquee, ArmaanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cologna, Camila TakenoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Craemer, SamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dolman, EmmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartenhagen, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Vloed, FannyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanders, EllenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eggermont, AlineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bekaert, Sarah-LeeUNSPECIFIEDorcid.org/0000-0002-4769-3460UNSPECIFIED
Van Loocke, WouterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bek, Jan WillemUNSPECIFIEDorcid.org/0000-0003-1337-1970UNSPECIFIED
Dewyn, GivaniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loontiens, SiebeUNSPECIFIEDorcid.org/0000-0002-4602-4580UNSPECIFIED
Van Isterdael, GertUNSPECIFIEDorcid.org/0000-0001-6626-1316UNSPECIFIED
Decaesteker, BiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tilleman, LaurentijnUNSPECIFIEDorcid.org/0000-0001-7584-1179UNSPECIFIED
Van Nieuwerburgh, FilipUNSPECIFIEDorcid.org/0000-0001-8815-5485UNSPECIFIED
Vermeirssen, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Neste, ChristopheUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ghesquiere, BartUNSPECIFIEDorcid.org/0000-0003-1547-1705UNSPECIFIED
Goossens, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eyckerman, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Preter, KatleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houseley, JonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Molenaar, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Wilde, BramUNSPECIFIEDorcid.org/0000-0003-0213-1322UNSPECIFIED
Roberts, Stephen S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Durinck, KaatUNSPECIFIEDorcid.org/0000-0003-1762-5739UNSPECIFIED
Speleman, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-690083
DOI: 10.1126/sciadv.abn1382
Journal or Publication Title: Sci. Adv.
Volume: 8
Number: 28
Date: 2022
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 2375-2548
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PANCREATIC-CANCER CELLS; REPLICATION STRESS; THERAPEUTIC TARGET; ADVANCED-STAGE; DNA-DAMAGE; S-PHASE; GEMCITABINE; EXPRESSION; ALK; ATRMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69008

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