(P 27) SUMO2 INHIBITION REVERSES ABERRANT EPIGENETIC REWIRING DRIVEN BY SYNOVIAL SARCOMA FUSION ONCOPROTEINS AND IMPAIRS SARCOMAGENESIS

Objective: Synovial sarcoma (SySa) is an aggressive soft tissue sarcoma that lacks effective targeted therapies. The SS18-SSX fusion protein drives oncogenesis by altering transcriptional programs, which we hypothesize creates unique vulnerabilities that can be exploited therapeutically, making it a promising target for treatment.

Methods: We utilized in vitro as well as in vivo CRISPR screens along with transcriptomic and chromatin occupancy studies to identify genes that are selective dependent in SySa. Small molecule inhibitor studies were employed across several human SySa cell lines harboring distinct SS18-SSX fusions. The impact of these treatments on cell proliferation and apoptosis was assessed through cell viability assays, annexin V staining, etc.. Additionally, in vivo studies were conducted using transplant models of SySa in nude mice to measure tumor growth and molecular changes in the presence of the inhibitor.

Results: SUMO2 was identified as a critical vulnerability in SySa cells through functional genomic screens. TAK-981, a specific small molecule inhibitor of SUMO2/3 conjugation significantly reduced the growth and colony-forming ability of SySa cell lines, inducing apoptosis and S-phase arrest. Transcriptomic analysis revealed that TAK-981 reversed the SS18-SSX-driven oncogenic program, downregulating key pathways, including cell cycle-associated genes and doxorubicin resistant genes. Notably, SUMO2 inhibition reduced SS18-SSX protein levels and chromatin occupancy, leading to a reduction in H2AK119 ubiquitination, a mark associated with SS18-SSX activity. In vivo, TAK-981 treatment markedly impaired SySa tumor growth without significant toxicity.

Conclusion: This study identifies SUMO2 inhibition as a potential therapeutic strategy in SySa by disrupting SS18-SSX-mediated oncogenesis. Given that TAK-981 is already in clinical trials for other cancers, our findings present an opportunity for its repurposing in synovial sarcoma, offering a promising avenue for targeted therapy.