RUVBL1 and RUVBL2 are druggable MYCN regulators in neuroblastoma

High-risk neuroblastoma (NB), accounting for approximately 50% of all cases, exhibits high relapse rates and life-threatening toxicities despite intensive therapies, highlighting the need for safer and more effective treatments. Analysis of publicly available NB transcriptomic datasets identified RUVBL2 as a key node in the MYC(N) regulatory network. High MYC signature scores were observed in high-risk NB cohorts, and multivariate Cox regression analysis showed that RUVBL1/2 expression is an independent predictor of both overall and event-free survival. Experimental validation through cell culture, western blotting, qPCR, and RNA-seq demonstrated that knockdown or pharmacological inhibition of RUVBL1/2 using CB-6644 induced replication stress, leading to cell cycle arrest, DNA damage, and apoptosis. Mechanistically, RUVBL1/2 regulated ATR and ATM protein stability and transcriptionally controlled MYC(N) expression. These findings indicate that RUVBL1 and RUVBL2 are novel regulators of the DNA damage response with both therapeutic and prognostic potential in high-risk NB.