Neuroblastoma (NB) is a devastating childhood cancer with poor prognosis and limited options for novel precision therapies. Our teams (Ghent-Gothenburg) independently discovered the strong therapeutic potential of targeting DNA damage signaling (ATR-CHK1) by showing the value of sensitization of ATR/CHK1 drugging through combination with inhibition of enzyme component RRM2 implicated in DNA replication. In addition, durable responses were noted upon sequential ATR and ALK inhibition. NB are considered immunologically ‘cold’ tumors. However, targeting DNA damage signaling can induce strong immune-modulatory effects. Here, we join forces to further explore the RRM2/ATR-CHK1/ALK drugging axis to design novel treatment for NB through (1) in vitro comparison of two distinct RRM2 inhibitors on NB cells to select optimal drug combinations for testing in mice, (2) evaluate cellular and molecular responses to the selected drug combinations and determine the cellular composition and molecular responses of tumor cells and microenvironment under therapeutic pressure and (3) to develop a robust predictive gene signature for the therapy schemes as a prelude towards optimal selection of patients for clinical trials.