SUMO2 Inhibition Reverses Aberrant Epigenetic Rewiring Driven by Synovial Sarcoma Fusion Oncoproteins and Impairs Sarcomagenesis [CUT&RUN]

ABSTRACT: Synovial Sarcoma (SySa) is an aggressive soft tissue sarcoma that accounts for 5 – 10% of all soft tissue sarcomas. Current treatment involves radiation and radical surgery including limb amputation, highlighting the urgent need to develop targeted therapies. We reasoned that transcriptional rewiring by the fusion protein SS18-SSX, the sole oncogenic driver in SySa, creates specific vulnerabilities that can be exploited for treatment. To uncover genes that are selectively essential for SySa, we mined the Dependency Maps (Depmap) database to identify genes that specifically impact the fitness of SySa compared to other tumor cell lines. Targeted CRISPR library screening of select SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) was one of the strongest dependencies both in vitro as well as in vivo. TAK-981, a clinical-stage small molecule SUMO2 inhibitor potently inhibited growth, colony-forming ability, and spheroid formation of SySa cell lines. Strikingly, transcriptomic studies showed that TAK-981 treatment elicited a profound reversal of a gene expression program orchestrated by SS18-SSX fusions. Of note, genetic or pharmacological SUMO2 inhibition reduced global and chromatin levels of the SS18-SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic mark that is enhanced by the SySa fusions and plays an important role in SySa pathogenesis. Taken together, our studies identify SUMO2 as a novel, selective vulnerability in SySa. Since SUMO2 inhibitors are currently in Phase 1/2 clinical trials for human cancer, our findings present a novel potential avenue for targeted treatment of synovial sarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276071 | GEO | 2024/11/06

REPOSITORIES: GEO