Targeting replication stress in neuroblastoma by exploiting the synergistic potential of second generation RRM2 and CHK1 inhibitors

TL;DR

This study explores combining new RRM2 and CHK1 inhibitors to target replication stress in neuroblastoma and sarcoma cells, showing promising synergistic effects.

Contribution

The study introduces TAS1553 as a novel RRM2 inhibitor and demonstrates synergistic effects with CHK1 inhibitors in neuroblastoma and sarcoma models.

Findings

TAS1553 inhibits cell growth and increases replication stress, DNA damage, and apoptosis in tumor cells.

Combining TAS1553 with CHK1 inhibitors shows strong synergism in neuroblastoma and sarcoma cell lines and tumoroids.

Drug synergism is confirmed in a zebrafish xenograft model, supporting clinical potential.

Abstract

Tumor cells often cope with elevated levels of replication stress (RS) causing increased dependency on ATR-CHK1 signaling. We previously presented RRM2, the regulatory component of the ribonucleotide reductase (RNR) enzyme, as novel dependency in neuroblastoma (NB), in keeping with its role in RS resistance. We identified strong synergism for combined RRM2-CHK1 inhibition using the iron chelator triapine and prexasertib respectively. To obtain direct RNR targeting, we evaluated a novel inhibitor, TAS1553, specifically disrupting the RNR complex in this study. Treatment with TAS1553 impedes cell growth and induces enhanced RS, DNA damage and apoptosis. We demonstrated strong synergism between TAS1553 and the CHK1 inhibitors prexasertib and SRA737 in both NB cell lines and tumoroids as well as in sarcoma cell lines. We confirm drug synergism in vivo in a NB zebrafish xenograft model, further underscoring the broad clinical potential of combinatorial RRM2-CHK1 inhibition. Altogether, this study paves the way for further preclinical testing of second generation RRM2 and CHK1 inhibitors such as TAS1553 and SRA737 in neuroblastoma and sarcomas.

Figures