Novel therapeutic potential of the PARP inhibitor talazoparib in synovial sarcoma and its combined effect with ATR inhibitor.

BACKGROUND: Synovial sarcoma (SS) is a rare soft tissue sarcoma (STS) with limited treatment options, indicating the need for novel therapeutic strategies. In this study, we investigated the efficacy of talazoparib, a poly (ADP-ribose) polymerase enzyme (PARP) inhibitor, and DNA damage response (DDR) inhibitors in SS in vitro. METHODS: To investigate the target gene of talazoparib, we examined the mRNA expression of PARP1 and PARP16 in SS, using data from the Gene Expression Omnibus (GEO) database. Cell viability was assessed to evaluate the efficacy and antitumor effects of talazoparib and other drugs in multiple SS cell lines, using MTT assay. Additionally, flow cytometry-based annexin V assay and western blotting were performed to assess cell apoptosis and protein expression levels, respectively. RESULTS: mRNA expression of PARP16 was slightly higher in SS than other STS from GEO profile database. Talazoparib exerts anticancer effects against SS cells with high PARP16 expression by inducing apoptosis and DNA damage, on the other hand, the effects of talazoparib may be limited in SS cells with low PARP16 expression. Treatment with other DDR inhibitors, such as CHK1, WEE1, and ATR, suppressed the proliferation of SS cells. Celarasertib inhibited ATR phosphorylation and induced the cleavage of PARP and γH2AX, suggesting that celarasertib induced DNA damage and cell apoptosis. Combined therapy with talazoparib and ceralasertib exerts antitumor effects against SS cells through DNA damage and apoptosis pathways, suggesting a potential treatment strategy for SS. CONCLUSION: Talazoparib combined with ATR inhibitor possesses potential application as a therapeutic option for SS.