Konstantinos V. Floros, Carter K. Fairchild, Jinxiu Li, Kun Zhang, Jane L. Roberts, Richard Kurupi, Durga Paudel, Yanli Xing, Bin Hu, Vita Kraskauskiene, Nayyerehalsadat Hosseini, Shanwei Shen, Melissa M. Inge, Kyllie Smith-Fry, Li Li, Afroditi Sotiriou, Krista M. Dalton, Asha Jose, Elsamani I. Abdelfadiel, Ronald D. Hill, Jamie M. Slaughter, Mayuri Shende, Madelyn R. Lorenz, Noritaka Tanaka, Taisuke Kajino, Mary L. Nelson, Mandy R. Hinojosa, Victor A. Kehinde, Benjamin R. Belvin, Febri Gunawan Sugiokto, Zhao Lai, Alexandros C. Dimopoulos, Sosipatros A. Boikos, Angeliki M. Stamatouli, Janina P. Lewis, Masoud H. Manjili, Hiromichi Ebi, Kristoffer Valerie, Renfeng Li, Andrew Poklepovic, Jennifer E. Koblinski, Trevor Siggers, Ana Banito, Mikhail G. Dozmorov, Kevin B. Jones, Senthil K. Radhakrishnan, Anthony C. Faber
Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complexes and amplified expression of SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) complexes that drive an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program. The small molecule SUMOylation inhibitor, TAK-981, de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting SS models away from SS18::SSX-driven transcription. The result is DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergizes with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying an unappreciated role of SUMOylation in SS and a subsequent therapeutic vulnerability.