Targeting DCAF5 suppresses SMARCB1-mutant cancer via stabilizing SWI/SNF

While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and presents a conundrum for precision therapy because the proteins are no longer present. SMARCB1-mutant cancers epitomize this challenge because these highly lethal cancers are driven by inactivation of a single gene, a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to seek vulnerabilities, we contributed 16 SMARCB1-mutant cell lines to a near-genomewide CRISPR screen as part of the Cancer Dependency Map1-3. Here we report that the little-studied gene DCAF5 (DDB1-CUL4 Associated Factor 5) is a specific dependency in SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and in the absence of SMARCB1 DCAF5 causes degradation of incompletely assembled SWI/SNF complexes. Upon inhibition of DCAF5 SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore gene expression to levels sufficient to fully reverse the cancer state, including in a xenograft mouse model. Consequently, cancer results not from the loss of SMARCB1 function per se but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of DCAF5 may be sufficient to restore substantial SWI/SNF function and reverse cancer phenotypes caused by SMARCB1 loss. Overall design: ATAC-seq in G401 cells: shCTRL(n=3), shDCAF5(n=3) ATAC-Seq performed in triplicate in G401 cells treated with the combination of shDCAF5 with ATPase inhibitor BRM014 (1uM) with proper controls. Reprocessed ATAC-Seq data in triplicate for G401s with and without SMARCB1 added back Re-analysed Samples GSE210632/PRJNA866528 and processed data files: GSM6433872 SRX16881727 SAMN30167975 2112966_GFP_ATAC_n1.free* GSM6433873 SRX16881728 SAMN30167974 2118889_GFP_ATAC_n2.free* GSM6433874 SRX16881729 SAMN30167973 2161067_GFP_ATAC_n3.free* GSM6433875 SRX16881730 SAMN30167972 2112968_SMARCB1_ATAC_n1.free* GSM6433876 SRX16881719 SAMN30167971 2118891_SMARCB1_ATAC_n2.free* GSM6433877 SRX16881720 SAMN30167970 2161068_SMARCB1_ATAC_n3.free*