Synergistic inhibition of CHK1 and MUS81 to combat replication stress resistance in high-risk neuroblastoma.
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High-risk neuroblastoma is a pediatric tumor that originates from immature sympathetic neuroblasts and is characterized by a low mutational burden. Nevertheless, it frequently presents with highly recurrent chromosomal imbalances, including MYCN amplification and gain of chromosome 17q. Highly proliferative cancers, such as neuroblastoma, exhibit significant DNA replication stress, rendering tumor cells dependent on ATR-CHK1 signalling and DNA damage repair pathways. We previously hypothesized that gene dosage effects resulting from 17q copy number alterations of non-mutated genes involved in replication stress resistance could offer novel therapeutic opportunities. To identify critical candidate genes and pathways driving high-risk neuroblastoma, we performed an integrated bioinformatics analysis, and identified the BRIP1 gene, encoding the FANCJ protein, as top-ranked 17q candidate. FANCJ is involved in multiple processes that alleviate replication stress. In the absence of specific FANCJ-targeting compounds, we evaluated the phenotypic and molecular effects of pharmacological inhibition of the MUS81 endonuclease, which functions downstream of FANCJ in restarting stalled replication forks. When combined with CHK1 inhibition, we observed synergistic effects on neuroblastoma cell growth and survival, supporting further development of on-target MUS81 inhibitors for in vivo preclinical testing and future clinical trials aimed at overcoming replication stress resistance in high-risk neuroblastoma.