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

Leslie Duplaquet; Kevin So; Alexander W Ying; Shreoshi Pal Choudhuri; Xinyue Li; Grace D Xu; Yixiang Li; Xintao Qiu; Rong Li; Shilpa Singh; Xiaoli S Wu; Seth Hamilton; Victor D Chien; Qi Liu; Jun Qi; Tim D D Somerville; Hillary M Heiling; Emanuele Mazzola; Yenarae Lee; Thomas Zoller; Christopher R Vakoc; John G Doench; William C Forrester; Tinya Abrams; Henry W Long; Matthew J Niederst; Benjamin J Drapkin; Cigall Kadoch; Matthew G Oser

doi:10.1016/j.ccell.2024.06.012

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

Cancer Cell. 2024 Aug 12;42(8):1352-1369.e13. doi: 10.1016/j.ccell.2024.06.012. Epub 2024 Jul 18.

Authors

Leslie Duplaquet¹, Kevin So², Alexander W Ying³, Shreoshi Pal Choudhuri⁴, Xinyue Li¹, Grace D Xu⁵, Yixiang Li¹, Xintao Qiu⁶, Rong Li⁶, Shilpa Singh¹, Xiaoli S Wu⁷, Seth Hamilton⁴, Victor D Chien⁴, Qi Liu⁸, Jun Qi⁸, Tim D D Somerville⁹, Hillary M Heiling¹⁰, Emanuele Mazzola¹⁰, Yenarae Lee¹¹, Thomas Zoller⁹, Christopher R Vakoc⁷, John G Doench¹¹, William C Forrester⁹, Tinya Abrams⁹, Henry W Long⁶, Matthew J Niederst⁹, Benjamin J Drapkin⁴, Cigall Kadoch¹², Matthew G Oser¹³

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Biological and Biomedical Sciences Graduate Program, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
⁶ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA.
⁸ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Novartis BioMedical Research, Cambridge, MA 02139, USA.
¹⁰ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: [email protected].
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

PMID: 39029464
PMCID: PMC11494612 (available on 2025-08-12)
DOI: 10.1016/j.ccell.2024.06.012

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.

Keywords: BRD9; FHD-286; FHD-60; OCA-T1; OCA-T2; POU2F3; SMARCD1; mSWI/SNF; neuroendocrine; small cell lung cancer.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism
Gene Expression Regulation, Neoplastic*
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Mice
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / metabolism
Small Cell Lung Carcinoma* / drug therapy
Small Cell Lung Carcinoma* / genetics
Small Cell Lung Carcinoma* / metabolism
Small Cell Lung Carcinoma* / pathology
Transcription Factors* / genetics
Transcription Factors* / metabolism

Substances

Chromosomal Proteins, Non-Histone
Octamer Transcription Factor-3
SWI-SNF-B chromatin-remodeling complex
Transcription Factors
POU2F3 protein, human

Abstract

MeSH terms

Substances

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