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

Duplaquet, Leslie, So, Kevin, Ying, Alexander W, Pal Choudhuri, Shreoshi, Li, Xinyue, Xu, Grace D, Li, Yixiang, Qiu, Xintao, Li, Rong, Singh, Shilpa, Wu, Xiaoli S, Hamilton, Seth, Chien, Victor D, Liu, Qi, Qi, Jun, Somerville, Tim DD, Heiling, Hillary M, Mazzola, Emanuele, Lee, Yenarae, Zoller, Thomas, Vakoc, Christopher R, Doench, John G, Forrester, William C, Abrams, Tinya, Long, Henry W, Niederst, Matthew J, Drapkin, Benjamin J, Kadoch, Cigall, Oser, Matthew G (July 2024) Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer. Cancer Cell. S1535-6108(24)00237. ISSN 1535-6108 (Public Dataset)

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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.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > lung cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Vakoc, Christopher R.
Communities:	CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Vakoc lab CSHL Cancer Center Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	17 July 2024
Date Deposited:	23 Jul 2024 14:09
Last Modified:	23 Jul 2024 14:09
Related URLs:	Publisher
Dataset ID:	GEO: GSE249362 GEO: GSE249258
URI:	https://repository.cshl.edu/id/eprint/41620

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