The selective RRM2 inhibitor TAS1553 is synergistic with multiple CHK1 inhibitors in neuroblastoma

Tumor cells experience high replication stress, driving genomic instability. Recent studies reveal that neuroblastoma, a pediatric tumor, heavily relies on the ATR-CHK1 signaling pathway. Our prior work identified RRM2, part of the ribonucleotide reductase (RNR) complex, as a key target in neuroblastoma. In this study, we assessed the effects of the RNR-disrupting compound TAS1553 on neuroblastoma cells. Both in vitro and in vivo, TAS1553 inhibited cell growth and triggered apoptosis. Additionally, TAS1553 synergized with CHK1 inhibitors prexasertib and SRA737, increasing replication stress and DNA damage. We also observed these effects in Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. Notably, TAS1553 downregulated RNA splicing factors, suggesting potential for combination therapies with splicing inhibitors. Overall design: Neuroblastoma cells (IMR32 and CLBGA) were treated with TAS1553, SRA737, prexasertib and DMSO. Three or four biological replicates.