Floros Konstantinos V, Fairchild Carter K, Li Jinxiu, Zhang Kun, Roberts Jane L, Kurupi Richard, Hu Bin, Kraskauskiene Vita, Hosseini Nayyerehsadat, Shen Shanwei, Inge Melissa M, Smith-Fry Kylie, Li Li, Sotiriou Afroditi, Dalton Krista M, Jose Asha, Abdelfadiel Elsamani I, Xing Yanli, Hill Ronald D, Slaughter Jamie M, Shende Mayuri, Lorenz Madelyn R, Hinojosa Mandy R, Belvin Benjamin R, Lai Zhao, Boikos Sosipatros A, Stamatouli Angeliki M, Lewis Janina P, Manjili Masoud H, Valerie Kristoffer, Li Renfeng, Banito Ana, Poklepovic Andrew, Koblinski Jennifer E, Siggers Trevor, Dozmorov Mikhail G, Jones Kevin B, Radhakrishnan Senthil K, Faber Anthony C
bioRxiv. 2024 Apr 27:2024.04.25.591023. doi: 10.1101/2024.04.25.591023.
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.
滑膜肉瘤（SS）由SS18::SSX融合癌蛋白驱动，最终对治疗方法具有难治性。SS18::SSX改变ATP依赖的染色质重塑BAF（哺乳动物SWI/SNF）复合物，导致经典（cBAF）复合物降解，并使含SS18::SSX的非经典BAF（ncBAF或GBAF）大量存在，后者驱动SS特异性转录程序和肿瘤发生。我们证明SS18::SSX激活SUMO化程序，且滑膜肉瘤对小分子SAE1/2抑制剂TAK-981敏感。从机制上讲，TAK-981使cBAF亚基SMARCE1去SUMO化，稳定并恢复染色质上的cBAF，远离由SS18::SSX-ncBAF驱动的转录，这与DNA损伤和细胞死亡相关，并在人和小鼠滑膜肉瘤肿瘤模型中均导致肿瘤抑制。TAK-981通过增加DNA损伤与细胞毒性化疗协同作用，导致肿瘤消退。靶向滑膜肉瘤中的SUMO化途径可恢复cBAF复合物并阻断SS18::SSX-ncBAF转录组，确定了滑膜肉瘤中的治疗弱点，使临床用TAK-981能够治疗滑膜肉瘤。
