Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient-derived osteosarcoma cells and synergizes with cisplatin and talazoparib

Progress in the systemic management of osteosarcoma has been limited in recent decades, highlighting an urgent clinical need for novel treatment strategies. To address this, we have developed new preclinical models to evaluate promising agents for treating pediatric osteosarcoma. The checkpoint kinase (CHK) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have demonstrated activity against various malignancies, including sarcomas in both adults and children.

We tested the effectiveness of prexasertib in clonogenic survival assays using two new lines of primary patient-derived osteosarcoma cells and two established osteosarcoma cell lines. This was done both as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone significantly reduced clonogenic survival at low nanomolar concentrations, affecting cell cycle progression, inducing apoptosis, and causing double-stranded DNA breakage, all at levels well below clinically acceptable plasma concentrations.

When combined with cisplatin and talazoparib, prexasertib exhibited synergistic effects. Thus, CHK1 inhibition through prexasertib, in combination with DNA-damaging agents like cisplatin and PARP inhibitors, presents a potential new treatment option for pediatric osteosarcoma. These findings will now need to be validated in preclinical models derived from primary patient samples and through clinical trials.