Synergistic Inhibition of CHK1 and MUS81 to target replicative stress in high-risk neuroblastoma

Neuroblastoma (NB) is a pediatric tumor marked by genetic heterogeneity and frequent chromosomal alterations, including MYCN amplification and 17q gain, both linked to poor prognosis. These alterations affect key genes involved in transcriptional regulation and DNA damage response (DDR). NB cells experience high replicative stress (RS), making them particularly sensitive to DDR inhibition. Through integrative bioinformatics, genes such as EME1, RAD51C, and FANCJ on 17q were identified as critical in RS regulation. Targeting the downstream endonuclease MUS81, especially in combination with CHK1 inhibition, produced synergistic anti-tumor effects. This combination offers a promising strategy to exploit RS vulnerability in high-risk NB. Overall design: RNA-sequencing of high dose Dyngo4a and combination drugging of Dyngo4a and prexasertib in IMR-32 neuroblastoma cell lines.