Ribonucleotide Reductase Subunit Switching in Hepatoblastoma Drug Response and Relapse

Prognosis of children with high-risk hepatoblastoma (HB), the most common pediatric liver cancer, remains poor. In this study, we found ribonucleotide reductase (RNR) subunit M2 ( RRM2 ) was one of the key genes supporting cell proliferation in high-risk HB. While standard chemotherapies could effectively suppress RRM2 in HB cells, they induced a significant upregulation of the other RNR M2 subunit, RRM2B. Computational analysis revealed distinct signaling networks RRM2 and RRM2B were involved in HB patient tumors, with RRM2 supporting cell proliferation and RRM2B participating heavily in stress response pathways. Indeed, RRM2B upregulation in chemotherapy-treated HB cells promoted cell survival and subsequent relapse, during which RRM2B was gradually replaced back by RRM2. Combining an RRM2 inhibitor with chemotherapy showed an effective delaying of HB tumor relapse in vivo. Overall, our study revealed the distinct roles of the two RNR M2 subunits and their dynamic switching during HB cell proliferation and stress response. ### Competing Interest Statement The authors have declared no competing interest. * HB : hepatoblastoma HCC : hepatocellular carcinoma PDX : patient-derived xenografts RNR : ribonucleotide reductase RRM1 : ribonucleotide reductase subunit M1 RRM2 : ribonucleotide reductase subunit M2 RRM2B : ribonucleotide reductase subunit M2B NICD : Notch intercellular domain PNR : Prominin1CreERT2; RosaNICD1/+; RosaZsG PPTR : Prominin1CreERT2; Ptenflx/flx; Tp53flx/flx; RosaZsG tdT : tdTomato NSG : nod skid gamma TCGA : The cancer genome atlas GSEA : gene set enrichment analysis PYWAYRRM2 : ribonucleotide reductase subunit M2 associated pathways PYWAYRRM2B : ribonucleotide reductase subunit M2B associated pathways