Author:
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.
Abstract
AbstractSynovial 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.
Publisher
Cold Spring Harbor Laboratory