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

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. [Display omitted] •A positive selection genome-wide CRISPR-Cas9 screen identifies POU2F3 regulators•The mSWI/SNF complex maintains POU2F3 and its oncogenic program•Neuroendocrine (NE) status demarcates two subclasses of POU2F3+ SCLC•Non-NE POU2F3+ SCLCs are highly sensitive to SMARCA4/2 inhibitors and BRD9 degraders Duplaquet et al. use positive-selection CRISPR screening to identify that mSWI/SNF chromatin remodeler complexes regulate POU2F3 and its oncogenic program in SCLC and are required for POU2F3+ SCLC survival. Clinical-grade SMARCA4/2 inhibitors or BRD9 degraders demonstrate efficacy in POU2F3+ patient-derived and cell line xenograft models.