| 著者 |
Floros KV, Fairchild CK Jr, Li J, Zhang K, Roberts JL, Kurupi R, Paudel D, Xing Y, Hu B, Kraskauskiene V, Hosseini N, Shen S, Inge MM, Smith-Fry K, Li L, Sotiriou A, Dalton KM, Jose A, Abdelfadiel EI, Hill RD, Slaughter JM, Shende M, Lorenz MR, Tanaka N, Kajino T, Nelson ML, Hinojosa MR, Kehinde VA, Belvin BR, Sugiokto FG, Lai Z, Dimopoulos AC, Boikos SA, Stamatouli AM, Lewis JP, Manjili MH, Ebi H, Valerie K, Li R, Poklepovic A, Koblinski JE, Siggers T, Banito A, Dozmorov MG, Jones KB, Radhakrishnan SK, Faber AC.
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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) 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.
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