Abstract 7071: Pharmacological targeting of SUMOylation leads to cBAF complex stabilization and disruption of the synovial sarcoma signature

Abstract Synovial Sarcoma (SS) is driven by the SS18-SSX translocation event and occurs often in people under 30. In general, SS is refractory to chemotherapy and other therapeutic approaches. SS18-SSX does not directly bind to DNA but instead alters BAF complexes away from a wild-type SS18-containing cBAF complex towards a SS18-SSX- containing ncBAF complex to drive a SS-specific transcription program. Small molecule targeted therapies are expanding beyond the kinome, providing additional tools to treat cancers that are not yet amenable to targeted therapies. Here we demonstrate that SS18-SSX activates the SUMOylation program and SS are sensitive to the small molecule SAE1/2 inhibitor, subasumstat (TAK-981). Mechanistically, we demonstrate TAK-981 de-SUMOylates the cBAF/PBAF complex member, SMARCE1, leading to stabilization and restoration of cBAF complexes. This phenotypic shift leads to a DNA damage and cell death response, resulting in tumor inhibition across mouse models of SS. As such, TAK-981 combined with standard-of-care chemotherapy enhances SOC-induced DNA damage, leading to tumor regressions. Targeting the SUMOylation pathway in SS restores cBAF complexes, positioning it as a clinical candidate to treat this refractory cancer. Citation Format: Konstantinos V. Floros, Jinxiu Li, Jane L. Roberts, Richard Kurupi, Carter K. Fairchild, Bin Hu, Yanli Xing, Krista M. Dalton, Sosipatros A. Boikos, Angeliki M. Stamatouli, Mikhail G. Dozmorov, Jennifer E. Koblinski, Kevin B. Jones, Senthil K. Radhakrishnan, Anthony C. Faber. Pharmacological targeting of SUMOylation leads to cBAF complex stabilization and disruption of the synovial sarcoma signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7071.