A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation

Mammalian SWI/SNF chromatin remodeling complexes exist in three distinct, final-form assemblies: canonical BAF (cBAF), PBAF, and a newly-characterized non-canonical complex, ncBAF. However, their complex-specific targeting on chromatin, functions and roles in disease remain largely undefined. Here, we comprehensively mapped complex assemblies on chromatin and found that ncBAF complexes uniquely localize to CTCF sites and promoters. We identified ncBAF subunits as synthetic lethal targets specific to synovial sarcoma (SS) and malignant rhabdoid tumor (MRT), which share in common cBAF complex (SMARCB1 subunit) perturbation. Chemical and biological depletion of the BRD9 subunit of ncBAF rapidly attenuates SS and MRT cell proliferation. Notably, in cBAF-perturbed cancers, ncBAF complexes maintain gene expression at retained CTCF-promoter sites, and function in a manner distinct from fusion oncoprotein-bound complexes. Taken together, these findings unmask the unique chromatin targeting and function of ncBAF complexes and present new cancer-specific therapeutic targets.