RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition Journal Article
| Authors: | Nunes, C.; Depestel, L.; Mus, L.; Keller, K. M.; Delhaye, L.; Louwagie, A.; Rishfi, M.; Whale, A.; Kara, N.; Andrews, S. R.; Dela Cruz, F.; You, D.; Siddiquee, A.; Cologna, C. T.; De Craemer, S.; Dolman, E.; Bartenhagen, C.; De Vloed, F.; Sanders, E.; Eggermont, A.; Bekaert, S. L.; Van Loocke, W.; Bek, J. W.; Dewyn, G.; Loontiens, S.; Van Isterdael, G.; Decaesteker, B.; Tilleman, L.; Van Nieuwerburgh, F.; Vermeirssen, V.; Van Neste, C.; Ghesquiere, B.; Goossens, S.; Eyckerman, S.; De Preter, K.; Fischer, M.; Houseley, J.; Molenaar, J.; De Wilde, B.; Roberts, S. S.; Durinck, K.; Speleman, F. |
| Article Title: | 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. © 2022 The Authors, some rights reserved. |
| Keywords: | genes; cell culture; tumors; gene dosage; in-vitro; zebrafish; neuroblastomas; growth inhibition; high-risk neuroblastoma; ribonucleotide reductase; dna copy numbers; gain amplification; sympathetic nervous systems |
| Journal Title: | Science Advances |
| Volume: | 8 |
| Issue: | 28 |
| ISSN: | 2375-2548 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2022-07-15 |
| Start Page: | eabn1382 |
| Language: | English |
| DOI: | 10.1126/sciadv.abn1382 |
| PUBMED: | 35857500 |
| PROVIDER: | scopus |
| PMCID: | PMC9278860 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work