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

Floros, K. V.; Fairchild, C. K.; Li, J.; Zhang, K.; Roberts, J. L.; Kurupi, R.; Hu, B.; Kraskauskiene, V.; Hosseini, N.; Shen, S.; Inge, M. M.; Smith-Fry, K.; Li, L.; Sotiriou, A.; Dalton, K. M.; Jose, A.; Abdelfadiel, E. I.; Xing, Y.; Hill, R. D.; Slaughter, J. M.; Shende, M.; Lorenz, M. R.; Hinojosa, M. R.; Belvin, B. R.; Lai, Z.; Books, S. A.; Stamatouli, A. M.; Lewis, J. P.; Manjil, M. H.; Valerie, K.; Li, R.; Banito, A.; Poklepovic, A.; Koblinski, J.; Siggers, T.; Dozmorov, M. G.; Jones, K. B.; Radhakrishnan, S. K.; Faber, A. C.

doi:10.1101/2024.04.25.591023

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bioRxiv · 10.1101/2024.04.25.591023

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

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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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Floros, K. V., Fairchild, C. K., Li, J., Zhang, K., Roberts, J. L., Kurupi, R., Hu, B., Kraskauskiene, V., Hosseini, N., Shen, S., Inge, M. M., Smith-Fry, K., Li, L., Sotiriou, A., Dalton, K. M., Jose, A., Abdelfadiel, E. I., Xing, Y., Hill, R. D., Slaughter, J. M., Shende, M., Lorenz, M. R., Hinojosa, M. R., Belvin, B. R., Lai, Z., Books, S. A., Stamatouli, A. M., Lewis, J. P., Manjil, M. H., Valerie, K., Li, R., Banito, A., Poklepovic, A., Koblinski, J., Siggers, T., Dozmorov, M. G., Jones, K. B., Radhakrishnan, S. K., Faber, A. C.. 2024-04-27. Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma. https://doi.org/10.1101/2024.04.25.591023

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