BRD9 Degraders Unleash GBAF Chromatin Remodeling Activity in Synovial Sarcoma

作者：Jinxiu Li, Mary L. Nelson, Li Li, Xiaobo Xia, Christine Stephan, Katarzyna Modzelewska, Gary Yu, Iain Mulford, Honnappa Srinivas, Xinyi Ge, Sarah McCollum, Ewin R. Jones, Yixuan Guo, Xin Chen, Gregory Hollingworth, Thomas Zöller, Ensar Halilovic, Cedric R. Clapier, Aneasha F. Whittaker-Tademy, Faheem, Tinya Abrams, Edmund Harrington, Sofia Gkountela, Giorgio Giacomo Galli, Hans Voshol, Jason Thomas, Nathalie Carte, Xiaoyang Zhang, Katharine L. Diehl, David H. Lum, Martin Hirst, Jeffrey T. Yap, William C. Forrester, Bradley R. Cairns, Kevin B. Jones · 发表于：Cancer Research · 年份：2026 · DOI：10.1158/0008-5472.can-25-5405 · 研究领域：Chromatin Remodeling and Cancer、Protein Degradation and Inhibitors、Sarcoma Diagnosis and Treatment

Abstract Synovial sarcoma incorporates the SS18::SSX fusion oncoprotein into GLTSCR1-containing BRG1/BRM and associated factors (GBAF) complexes, which confers a dependency on the GBAF subunit BRD9. However, synovial sarcoma clinical trials with multiple BRD9 degraders failed to achieve clinically impactful remissions. In this study, we identified a mechanistic framework to explain these results. BRD9 depletion served to blunt proliferation in synovial sarcoma harboring minimal genomic alterations, rare in trial participants. In cultured cells, xenografts, and recombinant-purified complexes, BRD9 loss did not affect GBAF assembly. Although BRD9 degradation in synovial sarcoma reduced GBAF enrichment at target loci, BRD9-less complexes maintained or increased chromatin accessibility and associated gene transcription. Biochemical assays with purified recombinant GBAF demonstrated increased nucleosome sliding in the absence of BRD9. Together, these findings show that BRD9 restrains GBAF activity, with BRD9 degradation increasing enzymatic remodeling and target gene expression by fusion oncoprotein–distributed GBAFs in synovial sarcoma. This subtle epigenetic disturbance creates a low hurdle for synovial sarcoma to surpass, limiting the therapeutic efficacy of BRD9 degraders. Significance: BRD9 represses the GBAF chromatin remodeling complex, which causes enhanced rather than disrupted SS18::SSX complex activity following BRD9 degradation and explains the lack of efficacy of phar...