Nunes Carolina, Depestel Lisa, Mus Liselot, Keller Kaylee M, Delhaye Louis, Louwagie Amber, Rishfi Muhammad, Whale Alex, Kara Neesha, Andrews Simon R, Dela Cruz Filemon, You Daoqi, Siddiquee Armaan, Cologna Camila Takeno, De Craemer Sam, Dolman Emmy, Bartenhagen Christoph, De Vloed Fanny, Sanders Ellen, Eggermont Aline, Bekaert Sarah-Lee, Van Loocke Wouter, Bek Jan Willem, Dewyn Givani, Loontiens Siebe, Van Isterdael Gert, Decaesteker Bieke, Tilleman Laurentijn, Van Nieuwerburgh Filip, Vermeirssen Vanessa, Van Neste Christophe, Ghesquiere Bart, Goossens Steven, Eyckerman Sven, De Preter Katleen, Fischer Matthias, Houseley Jon, Molenaar Jan, De Wilde Bram, Roberts Stephen S, Durinck Kaat, Speleman Frank
Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
Sci Adv. 2022 Jul 15;8(28):eabn1382. doi: 10.1126/sciadv.abn1382. Epub 2022 Jul 13.
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.
高危神经母细胞瘤是一种起源于交感神经系统的儿科肿瘤，其突变负荷较低，但体细胞DNA拷贝数变异高度复发。此前，节段性增益和/或扩增有助于确定神经母细胞瘤发展的驱动因素。利用这种方法，结合基因剂量对表达和生存的影响，我们确定核糖核苷酸还原酶亚基M2（RRM2）为候选依赖因子，体外敲低RRM2后生长受到抑制以及在与人MYCN共表达人RRM2的神经母细胞瘤斑马鱼模型中肿瘤形成加速进一步支持了这一结论。强制诱导RRM2可减轻CHK1抑制诱导的过度复制应激，而人神经母细胞瘤中RRM2的高表达与CHK1的高活性相关。RRM2共过表达的MYCN驱动的斑马鱼肿瘤表现出差异表达的DNA修复基因，这与增强的ATR-CHK1信号活性一致。在体外，抑制RRM2会增强内在复制应激检查点成瘾性。最后，联合抑制RRM2和CHK1在高危神经母细胞瘤细胞系和患者来源的异种移植模型中具有协同作用，显示出治疗潜力。
