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 |
|---|---|
| Article number | eabn1382 |
| Pages (from-to) | 1-25 |
| Journal | Science advances |
| Volume | 8 |
| Issue number | 28 |
| DOIs | |
| Publication status | Published - Jul 2022 |
Bibliographical note
Funding Information:This work was supported by Research Foundation–Flanders 1197617N (to C.N.); Research Foundation–Flanders 11M1422N (to M.R.); Research Foundation–Flanders 3F014219 (to A.L.); Research Foundation–Flanders 1238420 (to B.D.); Bijzonder Onderzoeksfonds–ZAP (Ghent University) 202011/GE/ZAP/018 (to K.D.); Kom op Tegen Kanker (KOTK): “Preclinical evaluation of combined RRM2/DNA damage response signaling as therapy for high-risk neuroblastoma and entry point for sensitization to immunce checkpoint inhibition” (to F.S.); Stichting tegen Kanker (STK): “Novel combination therapies to combat therapy resistant neuroblastoma: Translating preclinical investigations to clinical trials” (to F.S.); Fight Kids Cancer: Replicative stress resistance modeling and therapeutic targeting in neuroblastoma (to F.S.); Innovative Training Networks (ITN): Validation of actionable genomic aberrations in a pediatric oncology network for doctorate students (to F.S.); and Olivia Hendrickx Research Fund (to F.S.). This research was funded, in part, through the “Geconcenteerde onderzoeksactie” (GOA), Ghent University: Replication fork protector dependency factors as novel targets for combination treatment and immunomodulation in neuroblastoma (BOF22/GOA/009) (to F.S. and S.E.). This research was funded, in part, through the GOA, Ghent University: Long non-coding RNAs in cancer: Deciphering the functional role of the dark matter of the human cancer genome (BOF16/GOA/023) (to F.S. and S.E.); Villa Joep (to F.S.); Wellcome Trust (110216) (to J.H. and A.W.); BBSRC (BI epigenetics ISP: BBS/E/B/000C0423) (to J.H.); MRC (iCASE studentship) (to N.K.); Artios Pharma (to N.K.); and UKRI-BBSCR (core capability grant) (to S.R.A.). This research was funded, in part, through NIH/NCI Cancer Center Support Grant P30 CA008748 (to S.S.R.). L.Del was funded by FWO (1S11817N) UGent BOF-GOA (BOF16/GOA/023). M.F. was supported by grants of the Deutsche Forschungsgemeinschaft (DFG; grant no. FI 1926/2-1 and as part of the SFB 1399) and the Förderverein für Krebskranke Kinder e.V. Köln (endowed chair).
Publisher Copyright:
© 2022 The Authors, some rights reserved.
Funding
This work was supported by Research Foundation–Flanders 1197617N (to C.N.); Research Foundation–Flanders 11M1422N (to M.R.); Research Foundation–Flanders 3F014219 (to A.L.); Research Foundation–Flanders 1238420 (to B.D.); Bijzonder Onderzoeksfonds–ZAP (Ghent University) 202011/GE/ZAP/018 (to K.D.); Kom op Tegen Kanker (KOTK): “Preclinical evaluation of combined RRM2/DNA damage response signaling as therapy for high-risk neuroblastoma and entry point for sensitization to immunce checkpoint inhibition” (to F.S.); Stichting tegen Kanker (STK): “Novel combination therapies to combat therapy resistant neuroblastoma: Translating preclinical investigations to clinical trials” (to F.S.); Fight Kids Cancer: Replicative stress resistance modeling and therapeutic targeting in neuroblastoma (to F.S.); Innovative Training Networks (ITN): Validation of actionable genomic aberrations in a pediatric oncology network for doctorate students (to F.S.); and Olivia Hendrickx Research Fund (to F.S.). This research was funded, in part, through the “Geconcenteerde onderzoeksactie” (GOA), Ghent University: Replication fork protector dependency factors as novel targets for combination treatment and immunomodulation in neuroblastoma (BOF22/GOA/009) (to F.S. and S.E.). This research was funded, in part, through the GOA, Ghent University: Long non-coding RNAs in cancer: Deciphering the functional role of the dark matter of the human cancer genome (BOF16/GOA/023) (to F.S. and S.E.); Villa Joep (to F.S.); Wellcome Trust (110216) (to J.H. and A.W.); BBSRC (BI epigenetics ISP: BBS/E/B/000C0423) (to J.H.); MRC (iCASE studentship) (to N.K.); Artios Pharma (to N.K.); and UKRI-BBSCR (core capability grant) (to S.R.A.). This research was funded, in part, through NIH/NCI Cancer Center Support Grant P30 CA008748 (to S.S.R.). L.Del was funded by FWO (1S11817N) UGent BOF-GOA (BOF16/GOA/023). M.F. was supported by grants of the Deutsche Forschungsgemeinschaft (DFG; grant no. FI 1926/2-1 and as part of the SFB 1399) and the Förderverein für Krebskranke Kinder e.V. Köln (endowed chair).