{"doi":"10.1016/j.ccell.2024.06.012","title":"Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer","abstract":"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.","journal":"Cancer Cell","year":2024,"id":418642,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1207110,"name":"Kevin Kam Fung So","orcid":"0000-0002-4846-7481","position":1,"is_corresponding":false},{"id":1207823,"name":"Alexander W. 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Chien","orcid":"0000-0003-0279-7239","position":12,"is_corresponding":false},{"id":323892,"name":"Qi Liu","orcid":"0000-0002-0839-8039","position":13,"is_corresponding":false},{"id":260598,"name":"Jun Qi","orcid":"0000-0002-1461-3356","position":14,"is_corresponding":false},{"id":266273,"name":"Tim D.D. Somerville","orcid":"0000-0002-6295-6126","position":15,"is_corresponding":false},{"id":673628,"name":"Hillary Heiling","orcid":"0000-0003-2654-3487","position":16,"is_corresponding":false},{"id":25323,"name":"Emanuele Mazzola","orcid":"0000-0003-0561-7336","position":17,"is_corresponding":false},{"id":806046,"name":"Yenarae Lee","orcid":null,"position":18,"is_corresponding":false},{"id":695645,"name":"Thomas Zöller","orcid":"0000-0002-9797-1692","position":19,"is_corresponding":false},{"id":251322,"name":"Christopher R. Vakoc","orcid":"0000-0002-1158-7180","position":20,"is_corresponding":false},{"id":54229,"name":"John G. Doench","orcid":"0000-0002-3707-9889","position":21,"is_corresponding":false},{"id":264565,"name":"William C. Forrester","orcid":"0000-0002-8640-8204","position":22,"is_corresponding":false},{"id":1207825,"name":"Tinya J. Abrams","orcid":null,"position":23,"is_corresponding":false},{"id":227618,"name":"Henry W. Long","orcid":"0000-0001-6849-6629","position":24,"is_corresponding":false},{"id":620642,"name":"Matthew J. Niederst","orcid":"0000-0002-7807-9586","position":25,"is_corresponding":false},{"id":302446,"name":"Benjamin J. Drapkin","orcid":"0000-0002-4824-7243","position":26,"is_corresponding":false},{"id":23989,"name":"Cigall Kadoch","orcid":"0000-0002-4058-5985","position":27,"is_corresponding":false},{"id":251320,"name":"Matthew G. 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