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

被引：22

作者：

Nunes, Carolina ^{[1
,2
]}

Depestel, Lisa ^{[1
,2
]}

Mus, Liselot ^{[1
,2
]}

Keller, Kaylee M. ^{[3
]}

Delhaye, Louis ^{[1
,2
,4
]}

Louwagie, Amber ^{[1
,2
]}

Rishfi, Muhammad ^{[1
,2
]}

Whale, Alex ^{[5
]}

Kara, Neesha ^{[5
]}

Andrews, Simon R. ^{[5
]}

Dela Cruz, Filemon ^{[6
]}

You, Daoqi ^{[6
]}

Siddiquee, Armaan ^{[6
]}

Cologna, Camila Takeno ^{[7
,8
]}

De Craemer, Sam ^{[7
,8
]}

Dolman, Emmy ^{[3
]}

Bartenhagen, Christoph ^{[9
,10
]}

De Vloed, Fanny ^{[1
,2
]}

Sanders, Ellen ^{[1
,2
]}

Eggermont, Aline ^{[1
,2
]}

Bekaert, Sarah-Lee ^{[1
]}

Van Loocke, Wouter ^{[1
,2
]}

Bek, Jan Willem ^{[1
,2
]}

Dewyn, Givani ^{[1
,2
]}

Loontiens, Siebe ^{[1
,2
]}

Van Isterdael, Gert ^{[11
]}

Decaesteker, Bieke ^{[1
,2
]}

Tilleman, Laurentijn ^{[12
]}

Van Nieuwerburgh, Filip ^{[12
]}

Vermeirssen, Vanessa ^{[1
,2
,13
]}

Van Neste, Christophe ^{[1
,2
]}

Ghesquiere, Bart ^{[7
,8
]}

Goossens, Steven ^{[1
,2
,14
]}

Eyckerman, Sven ^{[1
,2
,4
]}

De Preter, Katleen ^{[1
,2
]}

Fischer, Matthias ^{[9
,10
]}

Houseley, Jon ^{[5
]}

Molenaar, Jan ^{[3
]}

De Wilde, Bram ^{[1
,2
]}

Roberts, Stephen S. ^{[6
]}

Durinck, Kaat ^{[1
,2
]}

Speleman, Frank ^{[1
,2
]}

机构：

[1] Univ Ghent, Dept Biomol Med, Ghent, Belgium

[2] Canc Res Inst Ghent CRIG, Ghent, Belgium

[3] Princess Maxima Ctr, Utrecht, Netherlands

[4] Univ Ghent, VIB UGent Ctr Med Biotechnol, Ghent, Belgium

[5] Babraham Inst, Epigenet Programme, Cambridge, England

[6] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA

[7] VIB, Ctr Canc Biol CCB, Metabol Expertise Ctr, Leuven, Belgium

[8] Katholieke Univ Leuven, Dept Oncol, Metabol Expertise Ctr, Leuven, Belgium

[9] Univ Cologne, Med Fac, Ctr Mol Med Cologne, Cologne CMMC, Cologne, Germany

[10] Univ Childrens Hosp Cologne, Dept Expt Pediat Oncol, Cologne, Germany

[11] Univ Ghent, VIB Flow Core Facil, Ghent, Belgium

[12] Univ Ghent, Fac Pharmaceut Sci, NXTGNT, Ghent, Belgium

[13] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium

[14] Univ Ghent, Dept Diagnost Sci, Ghent, Belgium

来源：

SCIENCE ADVANCES | 2022年 / 8卷 / 28期

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

PANCREATIC-CANCER CELLS; REPLICATION STRESS; THERAPEUTIC TARGET; ADVANCED-STAGE; DNA-DAMAGE; S-PHASE; GEMCITABINE; EXPRESSION; ALK; ATR;

D O I：

10.1126/sciadv.abn1382

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：25

共 77 条

[1] Decreased FOXJ1 expression and its ciliogenesis programme in aggressive ependymoma and choroid plexus tumours [J].

Abedalthagafi, Malak S. ;

Wu, Michael P. ;

Merrill, Parker H. ;

Du, Ziming ;

Woo, Terri ;

Sheu, Shu-Hsien ;

Hurwitz, Shelley ;

Ligon, Keith L. ;

Santagata, Sandro .

JOURNAL OF PATHOLOGY, 2016, 238 (04) :584-597

[2] HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci [J].

Aird, Katherine M. ;

Iwasaki, Osamu ;

Kossenkov, Andrew V. ;

Tanizawa, Hideki ;

Fatkhutdinov, Nail ;

Bitler, Benjamin G. ;

Le, Linh ;

Alicea, Gretchen ;

Yang, Ting-Lin ;

Johnson, Brad ;

Noma, Ken-ichi ;

Zhang, Rugang .

JOURNAL OF CELL BIOLOGY, 2016, 215 (03) :325-334

[3] A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma [J].

Barbieri, Eveline ;

De Preter, Katleen ;

Capasso, Mario ;

Johansson, Peter ;

Man, Tsz-Kwong ;

Chen, Zaowen ;

Stowers, Paris ;

Tonini, Gian Paolo ;

Speleman, Frank ;

Shohet, Jason M. .

PLOS ONE, 2013, 8 (11)

[4] Newly-derived neuroblastoma cell lines propagated in serum-free media recapitulate the genotype and phenotype of primary neuroblastoma tumours [J].

Bate-Eya, Laurel T. ;

Ebus, Marli E. ;

Koster, Jan ;

den Hartog, Ilona J. M. ;

Zwijnenburg, Danny A. ;

Schild, Linda ;

van der Ploeg, Ida ;

Dolman, M. Emmy M. ;

Caron, Huib N. ;

Versteeg, Rogier ;

Molenaar, Jan J. .

EUROPEAN JOURNAL OF CANCER, 2014, 50 (03) :628-637

[5] MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma [J].

Beckers, Anneleen ;

Van Peer, Gert ;

Carter, Daniel R. ;

Gartlgruber, Moritz ;

Herrmann, Carl ;

Agarwal, Saurabh ;

Helsmoortel, Hetty H. ;

Althoff, Kristina ;

Molenaar, Jan J. ;

Cheung, Belamy B. ;

Schulte, Johannes H. ;

Benoit, Yves ;

Shohet, Jason M. ;

Westermann, Frank ;

Marshall, Glenn M. ;

Vandesompele, Jo ;

De Preter, Katleen ;

Speleman, Frank .

CANCER LETTERS, 2015, 366 (01) :123-132

[6] Differential Processing of let-7a Precursors Influences RRM2 Expression and Chemosensitivity in Pancreatic Cancer: Role of LIN-28 and SET Oncoprotein [J].

Bhutia, Yangzom Doma ;

Hung, Sau Wai ;

Krentz, Madeline ;

Patel, Dimal ;

Lovin, Dylan ;

Manoharan, Radhika ;

Thomson, J. Michael ;

Govindarajan, Rajgopal .

PLOS ONE, 2013, 8 (01)

[7]

Blosser Wayne D, 2020, Oncotarget, V11, P216, DOI 10.18632/oncotarget.27400

[8] Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase [J].

Buisson, Remi ;

Boisvert, Jessica L. ;

Benes, Cyril H. ;

Zou, Lee .

MOLECULAR CELL, 2015, 59 (06) :1011-1024

[9] Two sides of the Myc-induced DNA damage response: from tumor suppression to tumor maintenance [J].

Campaner, Stefano ;

Amati, Bruno .

CELL DIVISION, 2012, 7

[10] S phase-specific transcription of the mouse ribonucleotide reductase R2 gene requires both a proximal repressive E2F-binding site and an upstream promoter activating region [J].

Chabes, AL ;

Björklund, S ;

Thelander, L .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (11) :10796-10807

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