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

Carolina Nunes; 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 Ghesquiere; Steven Goossens; Sven Eyckerman; Katleen De Preter; Matthias Fischer; Jon Houseley; Jan Molenaar; Bram De Wilde; Stephen S. Roberts; Kaat Durinck; Frank Speleman

doi:10.1126/sciadv.abn1382

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

Carolina Nunes, 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 EggermontSarah 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 Ghesquiere, Steven Goossens, Sven Eyckerman, Katleen De Preter, Matthias Fischer, Jon Houseley, Jan Molenaar, Bram De Wilde, Stephen S. Roberts, Kaat Durinck, Frank Speleman

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	eabn1382
Journal	Science Advances
Volume	8
Issue number	28
DOIs	https://doi.org/10.1126/sciadv.abn1382
State	Published - Jul 2022
Externally published	Yes

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Nunes, C., Depestel, L., Mus, L., Keller, K. M., Delhaye, L., Louwagie, A., Rishfi, M., Whale, A., Kara, N., Andrews, S. R., Cruz, F. D., You, D., Siddiquee, A., Cologna, C. T., De Craemer, S., Dolman, E., Bartenhagen, C., De Vloed, F., Sanders, E., ... Speleman, F. (2022). RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition. Science Advances, 8(28), Article eabn1382. https://doi.org/10.1126/sciadv.abn1382

Nunes, C, Depestel, L, Mus, L, Keller, KM, Delhaye, L, Louwagie, A, Rishfi, M, Whale, A, Kara, N, Andrews, SR, Cruz, FD, You, D, Siddiquee, A, Cologna, CT, De Craemer, S, Dolman, E, Bartenhagen, C, De Vloed, F, Sanders, E, Eggermont, A, Bekaert, SL, Van Loocke, W, Bek, JW, 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, SS, Durinck, K & Speleman, F 2022, 'RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition', Science Advances, vol. 8, no. 28, eabn1382. https://doi.org/10.1126/sciadv.abn1382

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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.",

author = "Carolina Nunes and Lisa Depestel and Liselot Mus and Keller, {Kaylee M.} and Louis Delhaye and Amber Louwagie and Muhammad Rishfi and Alex Whale and Neesha Kara and Andrews, {Simon R.} and Cruz, {Filemon Dela} and Daoqi You and Armaan Siddiquee and Cologna, {Camila Takeno} and {De Craemer}, Sam and Emmy Dolman and Christoph Bartenhagen and {De Vloed}, Fanny and Ellen Sanders and Aline Eggermont and Bekaert, {Sarah Lee} and {Van Loocke}, Wouter and Bek, {Jan Willem} and Givani Dewyn and Siebe Loontiens and {Van Isterdael}, Gert and Bieke Decaesteker and Laurentijn Tilleman and {Van Nieuwerburgh}, Filip and Vanessa Vermeirssen and {Van Neste}, Christophe and Bart Ghesquiere and Steven Goossens and Sven Eyckerman and {De Preter}, Katleen and Matthias Fischer and Jon Houseley and Jan Molenaar and {De Wilde}, Bram and Roberts, {Stephen S.} and Kaat Durinck and Frank Speleman",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors, some rights reserved.",

year = "2022",

month = jul,

doi = "10.1126/sciadv.abn1382",

language = "English (US)",

volume = "8",

journal = "Science Advances",

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T1 - RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition

AU - Nunes, Carolina

AU - Depestel, Lisa

AU - Mus, Liselot

AU - Keller, Kaylee M.

AU - Delhaye, Louis

AU - Louwagie, Amber

AU - Rishfi, Muhammad

AU - Whale, Alex

AU - Kara, Neesha

AU - Andrews, Simon R.

AU - Cruz, Filemon Dela

AU - You, Daoqi

AU - Siddiquee, Armaan

AU - Cologna, Camila Takeno

AU - De Craemer, Sam

AU - Dolman, Emmy

AU - Bartenhagen, Christoph

AU - De Vloed, Fanny

AU - Sanders, Ellen

AU - Eggermont, Aline

AU - Bekaert, Sarah Lee

AU - Van Loocke, Wouter

AU - Bek, Jan Willem

AU - Dewyn, Givani

AU - Loontiens, Siebe

AU - Van Isterdael, Gert

AU - Decaesteker, Bieke

AU - Tilleman, Laurentijn

AU - Van Nieuwerburgh, Filip

AU - Vermeirssen, Vanessa

AU - Van Neste, Christophe

AU - Ghesquiere, Bart

AU - Goossens, Steven

AU - Eyckerman, Sven

AU - De Preter, Katleen

AU - Fischer, Matthias

AU - Houseley, Jon

AU - Molenaar, Jan

AU - De Wilde, Bram

AU - Roberts, Stephen S.

AU - Durinck, Kaat

AU - Speleman, Frank

PY - 2022/7

Y1 - 2022/7

N2 - 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.

AB - 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.

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U2 - 10.1126/sciadv.abn1382

DO - 10.1126/sciadv.abn1382

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AN - SCOPUS:85134258620

SN - 2375-2548

VL - 8

JO - Science Advances

JF - Science Advances

IS - 28

M1 - eabn1382

ER -

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

Abstract

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