RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition
- Author
- Carolina de Carvalho Nunes (UGent) , Lisa Depestel (UGent) , Liselot Mus (UGent) , Kaylee M. Keller, Louis Delhaye (UGent) , Amber Louwagie (UGent) , Muhammad Rishfi (UGent) , Alex Whale, Neesha Kara, Simon R. Andrews, Filemon Dela Cruz, Daoqi You, Armaan Siddiquee, Camila Takeno Cologna, Sam De Craemer, Emmy Dolman, Christoph Bartenhagen, Fanny De Vloed (UGent) , Ellen Sanders (UGent) , Aline Eggermont (UGent) , Sarah-Lee Bekaert (UGent) , Wouter Van Loocke (UGent) , Jan Willem Bek (UGent) , Givani Dewyn (UGent) , Siebe Loontiens (UGent) , Gert Van Isterdael (UGent) , Bieke Decaesteker (UGent) , Laurentijn Tilleman (UGent) , Filip Van Nieuwerburgh (UGent) , Vanessa Vermeirssen (UGent) , Christophe Van Neste (UGent) , Bart Ghesquière (UGent) , Steven Goossens (UGent) , Sven Eyckerman (UGent) , Katleen De Preter (UGent) , Matthias Fischer, Jon Houseley, Jan Molenaar, Bram De Wilde (UGent) , Stephen S. Roberts, Kaat Durinck (UGent) and Franki Speleman (UGent)
- Organization
- Project
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- RRM2 controlled replicative stress resistance as a druggable DNA copy number driven cell state in MYC(N) driven cancers
- Scrutinizing selective Aurora Kinase A inhibition as a novel entry point for synthetic lethality in neuroblastoma
- The role of super-enhancer regulated SOX11 in regulation of SWI/SNF and PRC2 activity in adrenergic neuroblastoma
- SOX11 as mediator of the adrenergic cell state in neuroblastoma: towards cell precision medicine
- Replication fork protector dependency factors: novel targets for combination treatment and immunomodulation in neuroblastoma (REINFORCE)
- Long noncoding RNAs in cancer: deciphering the functional role of the dark matter of the human cancer genome
- Programmable proximal protein labeling of long non-coding RNAs in cancer
- 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.
- Keywords
- Multidisciplinary
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8771191
- MLA
- de Carvalho Nunes, Carolina, et al. “RRM2 Enhances MYCN-Driven Neuroblastoma Formation and Acts as a Synergistic Target with CHK1 Inhibition.” SCIENCE ADVANCES, vol. 8, no. 28, 2022, doi:10.1126/sciadv.abn1382.
- APA
- de Carvalho Nunes, C., Depestel, L., Mus, L., Keller, K. M., Delhaye, L., Louwagie, A., … Speleman, F. (2022). RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition. SCIENCE ADVANCES, 8(28). https://doi.org/10.1126/sciadv.abn1382
- Chicago author-date
- Carvalho Nunes, Carolina de, Lisa Depestel, Liselot Mus, Kaylee M. Keller, Louis Delhaye, Amber Louwagie, Muhammad Rishfi, et al. 2022. “RRM2 Enhances MYCN-Driven Neuroblastoma Formation and Acts as a Synergistic Target with CHK1 Inhibition.” SCIENCE ADVANCES 8 (28). https://doi.org/10.1126/sciadv.abn1382.
- Chicago author-date (all authors)
- de Carvalho Nunes, Carolina, Lisa Depestel, Liselot Mus, Kaylee M. Keller, Louis Delhaye, Amber Louwagie, Muhammad Rishfi, Alex Whale, Neesha Kara, Simon R. Andrews, Filemon Dela Cruz, Daoqi You, Armaan Siddiquee, Camila Takeno Cologna, Sam De Craemer, Emmy Dolman, Christoph Bartenhagen, Fanny De Vloed, Ellen Sanders, Aline Eggermont, Sarah-Lee Bekaert, Wouter Van Loocke, Jan Willem Bek, Givani Dewyn, Siebe Loontiens, Gert Van Isterdael, Bieke Decaesteker, Laurentijn Tilleman, Filip Van Nieuwerburgh, Vanessa Vermeirssen, Christophe Van Neste, Bart Ghesquière, Steven Goossens, Sven Eyckerman, Katleen De Preter, Matthias Fischer, Jon Houseley, Jan Molenaar, Bram De Wilde, Stephen S. Roberts, Kaat Durinck, and Franki Speleman. 2022. “RRM2 Enhances MYCN-Driven Neuroblastoma Formation and Acts as a Synergistic Target with CHK1 Inhibition.” SCIENCE ADVANCES 8 (28). doi:10.1126/sciadv.abn1382.
- Vancouver
- 1.de Carvalho Nunes C, Depestel L, Mus L, Keller KM, Delhaye L, Louwagie A, et al. RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition. SCIENCE ADVANCES. 2022;8(28).
- IEEE
- [1]C. de Carvalho Nunes et al., “RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition,” SCIENCE ADVANCES, vol. 8, no. 28, 2022.
@article{8771191,
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.}},
articleno = {{eabn1382}},
author = {{de Carvalho Nunes, Carolina and Depestel, Lisa and Mus, Liselot and Keller, Kaylee M. and Delhaye, Louis and Louwagie, Amber and Rishfi, Muhammad and Whale, Alex and Kara, Neesha and Andrews, Simon R. and Dela Cruz, Filemon and You, Daoqi and Siddiquee, Armaan and Cologna, Camila Takeno and De Craemer, Sam and Dolman, Emmy and Bartenhagen, Christoph and De Vloed, Fanny and Sanders, Ellen and Eggermont, Aline and Bekaert, Sarah-Lee and Van Loocke, Wouter and Bek, Jan Willem and Dewyn, Givani and Loontiens, Siebe and Van Isterdael, Gert and Decaesteker, Bieke and Tilleman, Laurentijn and Van Nieuwerburgh, Filip and Vermeirssen, Vanessa and Van Neste, Christophe and Ghesquière, Bart and Goossens, Steven and Eyckerman, Sven and De Preter, Katleen and Fischer, Matthias and Houseley, Jon and Molenaar, Jan and De Wilde, Bram and Roberts, Stephen S. and Durinck, Kaat and Speleman, Franki}},
issn = {{2375-2548}},
journal = {{SCIENCE ADVANCES}},
keywords = {{Multidisciplinary}},
language = {{eng}},
number = {{28}},
pages = {{25}},
title = {{RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition}},
url = {{http://doi.org/10.1126/sciadv.abn1382}},
volume = {{8}},
year = {{2022}},
}
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