DNA-Dependent Protein Kinase Inhibitor Peposertib Potentiates the Cytotoxicity of Topoisomerase II Inhibitors in Synovial Sarcoma Models

Simple Summary This study focuses on finding improved treatment strategies for advanced or metastatic synovial sarcoma, which is a rare and aggressive type of soft tissue sarcoma. The researchers tested a combination of two drugs, peposertib and doxorubicin, to see if they could work together to kill synovial sarcoma cells more efficiently. The experiments conducted in cultured cancer cells and mouse models of synovial sarcoma demonstrated that when these drugs were used together, they had a significantly stronger effect against cancer cells compared to using either drug alone. It is noteworthy that the combination could successfully overcome resistance to doxorubicin monotherapy in a patient-derived tumor model. This study also shed light on the underlying molecular mechanisms of this combination effect. Overall, the findings suggest that combining peposertib with doxorubicin could be a promising treatment option for synovial sarcoma patients in the future.Abstract Synovial sarcoma is a rare and highly aggressive subtype of soft tissue sarcoma. The clinical challenge posed by advanced or metastatic synovial sarcoma, marked by limited treatment options and suboptimal outcomes, necessitates innovative approaches. The topoisomerase II (Topo II) inhibitor doxorubicin has remained the cornerstone systemic treatment for decades, and there is pressing need for improved therapeutic strategies for these patients. This study highlights the potential to enhance the cytotoxic effects of doxorubicin within well-characterized synovial sarcoma cell lines using the potent and selective DNA-PK inhibitor, peposertib. In vitro investigations unveil a p53-mediated synergistic anti-tumor effect when combining doxorubicin with peposertib. The in vitro findings were substantiated by pronounced anti-tumor effects in mice bearing subcutaneously implanted tumors. A well-tolerated regimen for the combined application was established using both pegylated liposomal doxorubicin (PLD) and unmodified doxorubicin. Notably, the combination of PLD and peposertib displayed enhanced anti-tumor efficacy compared to unmodified doxorubicin at equivalent doses, suggesting an improved therapeutic window-a critical consideration for clinical translation. Efficacy studies in two patient-derived xenograft models of synovial sarcoma, accurately reflecting human metastatic disease, further validate the potential of this combined therapy. These findings align with previous evidence showcasing the synergy between DNA-PK inhibition and Topo II inhibitors in diverse tumor models, including breast and ovarian cancers. Our study extends the potential utility of combined therapy to synovial sarcoma.