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[Preprint]. 2024 Apr 27:2024.04.25.591023. [Version 1] doi: 10.1101/2024.04.25.591023

Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma

Konstantinos V Floros, Carter K Fairchild, Jinxiu Li, Kun Zhang, Jane L Roberts, Richard Kurupi, Bin Hu, Vita Kraskauskiene, Nayyerehsadat Hosseini, Shanwei Shen, Melissa M Inge, Kylie Smith-Fry, Li Li, Afroditi Sotiriou, Krista M Dalton, Asha Jose, Elsamani I Abdelfadiel, Yanli Xing, Ronald D Hill, Jamie M Slaughter, Mayuri Shende, Madelyn R Lorenz, Mandy R Hinojosa, Benjamin R Belvin, Zhao Lai, Sosipatros A Boikos, Angeliki M Stamatouli, Janina P Lewis, Masoud H Manjili, Kristoffer Valerie, Renfeng Li, Ana Banito, Andrew Poklepovic, Jennifer E Koblinski, Trevor Siggers, Mikhail G Dozmorov, Kevin B Jones, Senthil K Radhakrishnan, Anthony C Faber
PMCID: PMC11071469  PMID: 38712286

Abstract

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) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized 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-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

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