Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis.

ABSTRACT: Synovial sarcoma (SySa) is an aggressive soft tissue sarcoma with an urgent need to develop targeted therapies. Here, we exploited specific vulnerabilities created by transcriptional rewiring by the fusion protein SS18::SSX, the sole oncogenic driver in SySa. To uncover genes that are selectively essential for the fitness of SySa cells compared to other tumor cell lines, we mined  the Cancer-Dependency-Map data. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) constituted one of the strongest dependencies both in vitro and in vivo. TAK-981, a clinical-stage small-molecule SUMO2 inhibitor potently suppressed growth and colony-forming ability. Transcriptomic profiling showed that SUMO2 inhibition elicited a profound reve

SUBMITTER: Iyer R 

PROVIDER: S-EPMC12436642 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature