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

Autor:	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.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2024 Aug 12; Vol. 42 (8), pp. 1352-1369.e13. Date of Electronic Publication: 2024 Jul 18.
DOI:	10.1016/j.ccell.2024.06.012
Abstrakt:	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. Competing Interests: Declaration of interests M.G.O. reports grants from Eli Lilly, Takeda, Novartis, BMS, and Circle Pharma. C.K. is the Scientific Founder, Scientific Advisor to the Board of Directors, Scientific Advisory Board member, shareholder, and consultant for Foghorn Therapeutics, Inc. (Cambridge, MA), serves on the Scientific Advisory Boards of Nereid Therapeutics, Nested Therapeutics, and and Fibrogen, Inc. and is a consultant for Cell Signaling Technologies, Accent Therapeutics, and Google Ventures. C.K. is also a member of the Molecular Cell and Cell Chemical Biology Editorial Boards. B.J.D. has received consulting fees from AstraZeneca, Sonata Therapeutics and Dialectic Therapeutics. C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals and Treeline Biosciences; has received research funding from Boehringer-Ingelheim and Treeline Biosciences; and owns stock in Treeline Biosciences. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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