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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 D D; 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.
  • Duplaquet L; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • So K; 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.
  • Ying AW; 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.
  • Pal Choudhuri S; 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.
  • Li X; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Xu GD; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
  • Li Y; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Qiu X; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Li R; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Singh S; Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • Wu XS; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA.
  • Hamilton S; 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.
  • Chien VD; 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.
  • Liu Q; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Qi J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Somerville TDD; Novartis BioMedical Research, Cambridge, MA 02139, USA.
  • Heiling HM; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Mazzola E; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Lee Y; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Zoller T; Novartis BioMedical Research, Cambridge, MA 02139, USA.
  • Vakoc CR; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA.
  • Doench JG; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Forrester WC; Novartis BioMedical Research, Cambridge, MA 02139, USA.
  • Abrams T; Novartis BioMedical Research, Cambridge, MA 02139, USA.
  • Long HW; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Niederst MJ; Novartis BioMedical Research, Cambridge, MA 02139, USA.
  • Drapkin BJ; 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.
  • Kadoch C; 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: cigall_kadoch@dfci.harvard.edu.
  • Oser MG; 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: matthew_oser@dfci.harvard.edu.
Cancer Cell ; 42(8): 1352-1369.e13, 2024 Aug 12.
Article en En | MEDLINE | ID: mdl-39029464
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Factores de Transcripción / Regulación Neoplásica de la Expresión Génica / Carcinoma Pulmonar de Células Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Factores de Transcripción / Regulación Neoplásica de la Expresión Génica / Carcinoma Pulmonar de Células Pequeñas / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article