GSE161899 The dependency factor RRM2 at the nexus of a copy number driven regulatory network and a target for synthetic lethal interactions with replication stress checkpoint addiction in high-risk neuroblastoma [siRNA_RRM2]

In this study, we identified and functionally evaluated the ‘ribonucleotide reductase regulatory subunit 2’ (RRM2) as a top-ranked 2p putative co-driver and therapeutic target in high-risk neuroblastoma enforcing replicative stress resistance. RRM2 dependency was shown in vitro through knockdown in neuroblastoma cells, with transcriptome analysis reveali ng downregulation of pediatric tumor markers. Transgenic zebrafish lines expressing RRM2 in immature sympathoblasts were crossed with a dh-MYCN transgenic zebrafish line, with RRM2 overexpression dramatically increasing tumor penetrance from 20% to nearly 100%, accelerating neuroblastoma formatio n with tumors formed as early as 5 weeks of age in the double positive fish. Through CasID, we aimed to identify RRM2 promotor bound proteins. and enriched amongst others HEXIM1 and the NurRD complex. Importantly, adaptive responses regulating RRM2 expression are also controlled by ATR/CHK1 and WEE 1 cell cycle checkpoint kinases, as shown by pharmacological inhibition with small molecule inhibitors. We provide in vitro and in vivo data showing that RRM2 inhibition with triapine strongly sensitizes neuroblastoma cells to CHK1 inhibition and that combined treatment could robustly induce upregul ated PD-L1 surface expression. Altogether, we propose RRM2 as a bona fide target to explore novel synergistic drug combinations through phase I clinical trials.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research