DNA repair and replicative stress addiction in neuroblastoma

Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system. Survival remains poor for the almost 40 % of patients with high-risk NB. Targeted therapy options for high-risk NB are limited and single compound strategies often fail due to escape mechanisms, driven either by tumor heterogeneity or adaptive (epigenetic) responses or mutations. Novel NB therapeutic approaches rely increasingly on biomarker selected cohorts for phase I/II clinical trials. Parallel intensive research programs are needed to identify novel therapeutic vulnerabilities or drug targeting strategies and to further inform clinical trials and prioritize potent, less toxic combinations. While several effective chemotherapies work by increasing replication stress in cancer cells, recently, newer putatively less toxic small molecule-based approaches that directly target DNA damage response (DDR) pathway components such as ATR, CHK1 and PARP inhibitors are being evaluated in early phase trials for many cancers. NB sequencing studies have identified recurrent alterations (copy number and mutations) in many of these genes encoding critical DDR pathway proteins suggesting susceptibility to specific classes of DDR-targeting therapies. In this review, we summarize current data supporting the roles of DDR and replicative stress addiction in NB, including genetic alterations which impact DDR signaling pathways. Finally, we review the mechanisms, pre-clinical evidence and ongoing trials for drugs that target DDR-deficient and/or replication addicted NB.