Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer

Small cell lung cancers (SCLC) are comprised of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLC, ~12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities for this subtype. Here using genome-scale CRISPR/Cas9-based screens reporting on POU2F3 expression in SCLC cell lines, we define mSWI/SNF complexes, including non-canonical BAF complexes (ncBAF), as top regulators of POU2F3 and dependencies specific to the POU2F3-positive subtype. Notably, clinical-grade pharmacologic mSWI/SNF complex inhibition attenuates proliferation of all POU2F3-positive SCLCs, while disruption of ncBAF via BRD9 degradation is uniquely effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF complexes maintain accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, chemical targeting of SMARCA4/2 mSWI/SNF ATPases and BRD9 decrease POU2F3-SCLC tumor growth and increase survival in vivo. Taken together, these results define mSWI/SNF-mediated global governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy in SCLC. Overall design: Comparative gene expression profiling analysis of RNA-seq data in 4 POU2F3-expressing human small cell lung cancer (SCLC) cell lines treated with a BRD9 degrader (WA-68-VQ71), a SMARCA2/4 inhibitor (BRM014) or DMSO