Abstract Synovial sarcoma (SyS) incorporates the SS18::SSX fusion oncoprotein into GLTSCR1-containing BRG1/BRM and associated factors (GBAF) complexes, and demonstrated a dependency on GBAF subunit, BRD9. However, SyS clinical trials with multiple BRD9 degraders failed to achieve clinically impactful remissions. Here, we provide a mechanistic framework to explain these results. BRD9 depletion serves to blunt proliferation in SySs harboring minimal genomic alterations, rare in trial participants. In cultured cells, xenografts, and recombinant purified complexes, BRD9 loss does not impact GBAF assembly. Although BRD9 degradation in SyS reduces GBAF enrichment at target loci, BRD9-less complexes maintain or increase chromatin accessibility and associated gene transcription. Biochemical assays with purified recombinant GBAF demonstrate markedly increased nucleosome sliding in the absence of BRD9. Thus, BRD9 restrains GBAF activity, with BRD9 degradation increasing enzymatic remodeling and target gene expression by fusion oncoprotein-distributed GBAFs in SyS. This subtle epigenetic disturbance creates a low hurdle for SyS to surpass. Citation Format: Jinxiu Li, Mary Nelson, Li Li, Xiaobo Xia, Christine Stephan, Katarzyna Modzelewska, Gary Yu, Iain Mulford, Honnappa Srinivas, Xinyi Ge, Sarah McCollum, Ewin R Jones, Yixuan Guo, Xi Chen, Thomas Zoller, Gregory Hollingworth, Ensar Halilovic, Tinya J. Abrams, Edmund Harrington, Sofia Gkountela, Giorgio Galli, Hans Voshol, Nathalie Carte, Jason Thomas, Xiaoyang Zhang, David Lum, Martin Hirst, Jeffery Yap, William Forrester, Bradley R. Cairns, Kevin Bruce Jones. BRD9 functions as a negative regulator of GBAF in synovial sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3499.

Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.

Supplementary Table 3: A total of 246 cell lines were evaluated for both SHP2 knockdown and SHP099 sensitivity. Data displays PTPN11 shRNA ATARIS Quantile Score and SHP099 IC50 and Amax for each cell line tested.

PDF file - 77KB, Pharmacodynamic effects of LFA102 in the rat mammary gland

Supplementary Table 4: List of cell lines evaluated for sensitivity to SHP099 (Tab 1) or an RTK-inhibitor (Tab 2) in 2D or 3D. Included is the lineage and the KRAS mutation status. Where data are blank, no viable data was available, or the cell line did not grow appropriately as a tumor spheroid.

(A) Immunoblot of p-RSK3 and qPCR for DUSP6 from MIA PaCa-2 xenografts collected 3 hours after the last dose from Fig 5C. (B) Immunoblot for the designated proteins from MIA PaCa-2 cells grown in 2D, 3D and from in vivo xenografts without compound treatment. Protein loading amount was normalized and verified by tubulin loading control. Each separate column represents an individual treated tumor. (C) Dependency of MET by DRIVE pooled shRNA screen (y axis, ATARIS Quantile score of less than -0.5 indicates a significant effect) and expression of HGF (x-axis) by RNAseq in pancreatic cancer cell lines in CCLE (n=21). (D) Immunoblot of p-RSK3 and qPCR for DUSP6 from KP4 xenografts collected 3 hours after the last dose from Fig 5E. Protein loading amount was normalized and verified by tubulin loading control. Each separate column represents an individual treated tumor (E) Immunoblot for the designated proteins from KP4 cells grown in 2D, 3D and from in vivo xenografts without compound treatment (F) Schematic of RTK-SHP2 signaling highlighting that SHP2 acts downstream of one or more activated RTKs to elicit downstream signaling in KRAS mutant and also additional SHP2-specific, non-MAPK signaling. SHP2 inhibition by SHP099 can serve as a surrogate for cancers where KRAS mutant cancers are dependent on upstream RTKs.

Supplementary Data from Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia

Cell line sensitivity table

Additional small molecule inhibition of LMJ729/LOP628-mediated degranulation

Supplementary Material and Methods. File contains the following: Transcriptome sequencing and analysis, Soft agar assay, 2D and 3D Cell proliferation screen and compound characterization information.

PDF file - 59KB, Correlation between serum LFA102 and serum PRL over time in rats

FcgR1/FcgR3 gene expression analysis of in vitro generated mast cells

F(ab')2-LMJ729 degranulation assay of hIFNg-treated mast cells

Representative FACs staining of in vitro generated mast cells confirming maturation

The activity of nazartinib, TNO155, and their combination in EGFR mutant NSCLC cell lines.

The synergy in the MAPK pathway suppression and anti-proliferation effect by KRASG12C inhibitor and TNO155.

PDF file - 55KB, Pharmacokinetic properties of LFA102 in rodents