Neuroblastoma (NB) is an extra-cranial pediatric tumor that arises from immature precursor cells that normally give rise to the sympathetic nervous system. Improving survival and reducing long-term toxicity are urgent medical needs requiring novel, more effective and less toxic therapeutic anti-cancer agents. We recently showed that RRM2 activity increases replicative stress and strongly enhances the synthetic lethal MYCN-CHK1 interaction and reported ALK as upstream regulator of the ATR-CHK1 replicative stress checkpoint signaling axis with unexpected durable responses in combined ALK-ATR inhibition drugging in genetic NB models. We aim to gain further insight into the role of the ALK-ATR-CHK1-RRM2 signaling axis in neuroblastoma. To achieve this, we aim to (1) execute an in vitro exploration of RRM2 and ALK inhibition as modulators of ATR- CHK1 drug responses and (2) perform an integrated single cell and spatial omics analyses of ALK signaling inhibition in sustained ATR-CHK1 drug responses.