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Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer.
de Miguel, Fernando J; Gentile, Claudia; Feng, William W; Silva, Shannon J; Sankar, Akshay; Exposito, Francisco; Cai, Wesley L; Melnick, Mary Ann; Robles-Oteiza, Camila; Hinkley, Madeline M; Tsai, Jeanelle A; Hartley, Antja-Voy; Wei, Jin; Wurtz, Anna; Li, Fangyong; Toki, Maria I; Rimm, David L; Homer, Robert; Wilen, Craig B; Xiao, Andrew Z; Qi, Jun; Yan, Qin; Nguyen, Don X; Jänne, Pasi A; Kadoch, Cigall; Politi, Katerina A.
Afiliación
  • de Miguel FJ; Yale Cancer Center, New Haven, CT 06520, USA.
  • Gentile 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.
  • Feng WW; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Silva SJ; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Sankar A; 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.
  • Exposito F; Yale Cancer Center, New Haven, CT 06520, USA.
  • Cai WL; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Melnick MA; Yale Cancer Center, New Haven, CT 06520, USA.
  • Robles-Oteiza C; Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Hinkley MM; 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.
  • Tsai JA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Hartley AV; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Wei J; Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Laboratory Medicine, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Wurtz A; Yale Cancer Center, New Haven, CT 06520, USA.
  • Li F; Yale Center for Analytical Sciences, Yale School of Public Health, Laboratory of Epidemiology and Public Health, 60 College St, New Haven, CT 06510, USA.
  • Toki MI; Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Rimm DL; Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Homer R; Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Wilen CB; Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Laboratory Medicine, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Xiao AZ; Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Qi J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Yan Q; Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
  • Nguyen DX; Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale School of M
  • Jänne PA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, 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.
  • Politi KA; Yale Cancer Center, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, Yale University, New Haven, CT 06510, USA; Yale Stem Cell Center, Yale School of M
Cancer Cell ; 41(8): 1516-1534.e9, 2023 08 14.
Article en En | MEDLINE | ID: mdl-37541244
Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos