Therapeutic Potential of Bromodomain and Extra-Terminal Domain Inhibitors for Synovial Sarcoma Cells

Synovial sarcoma (SS) is a rare subtype of soft-tissue sarcoma characterized by the expression of the fusion gene SS18-SSX, primarily affecting the extremities of young patients. Current anticancer treatments show limited effectiveness against this malignancy, highlighting the need for new therapeutic strategies. Given the established role of SS18-SSX in epigenetic regulation, we investigated bromodomain and extra-terminal domain (BET) inhibitors and other epigenetic agents. Our study of the BET inhibitor ABBV-075 revealed significant antitumor effects, inducing G1-phase cell-cycle arrest and apoptosis in four SS cell lines. BET inhibitors demonstrated regulatory effects on key cell-cycle regulators, including MYC, p21, CDK4, and CDK6. Moreover, RNA sequencing analysis showed that changes in BCL2 family protein expression play a crucial role in apoptotic induction. Specifically, the expression ratio of the anti-apoptotic protein BCLxL to the pro-apoptotic protein BIM may influence susceptibility to ABBV-075. Furthermore, knockdown of SS18-SSX, which leads to increased BCL2 expression, reduced sensitivity to ABBV-075. These findings suggest that BET inhibitors targeting the SS18-SSX-regulated intrinsic apoptotic pathway could serve as a promising therapeutic strategy for synovial sarcoma.