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

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Synovial sarcoma (SS) is a rare soft-tissue malignancy primarily affecting young individuals.
• Current treatments for SS have limited efficacy, highlighting the need for novel therapeutic strategies.
• The SS18-SSX fusion gene plays a critical role in SS pathogenesis and epigenetic regulation.

Purpose of the Study:

• To investigate the therapeutic potential of bromodomain and extra-terminal domain (BET) inhibitors in synovial sarcoma.
• To elucidate the molecular mechanisms underlying the anti-tumor effects of BET inhibitors in SS.
• To explore the role of the SS18-SSX fusion gene in SS sensitivity to BET inhibition.

Main Methods:

• Utilized four SS cell lines for in vitro studies.
• Administered the BET inhibitor ABBV-075 to assess anti-tumor effects.
• Performed cell-cycle analysis, apoptosis assays, and RNA sequencing.
• Investigated the impact of SS18-SSX knockdown on drug sensitivity.

Main Results:

• ABBV-075 demonstrated significant anti-tumor activity, inducing G1 cell-cycle arrest and apoptosis in SS cell lines.
• BET inhibitors modulated key cell-cycle regulators including MYC, p21, CDK4, and CDK6.
• RNA sequencing revealed dynamic changes in BCL2 family protein expression, particularly the BCLxL/BIM ratio, correlating with apoptosis.
• SS18-SSX knockdown, which increases BCL2 expression, diminished sensitivity to ABBV-075.

Conclusions:

• BET inhibitors represent a promising therapeutic strategy for synovial sarcoma by targeting the SS18-SSX-regulated intrinsic apoptotic pathway.
• The expression ratio of BCLxL to BIM may predict patient response to BET inhibitor therapy.
• Targeting epigenetic dysregulation driven by SS18-SSX offers a novel approach for SS treatment.