BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency.

Autor:	Gupta M; Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.; Department of Genetics, Harvard Medical School, Boston, Massachusetts.; Biological and Biomedical Sciences PhD Program, Harvard University, Boston, Massachusetts., Concepcion CP; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts., Fahey CG; Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.; Department of Genetics, Harvard Medical School, Boston, Massachusetts., Keshishian H; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Bhutkar A; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts., Brainson CF; Markey Cancer Center, University of Kentucky, Lexington, Kentucky.; Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky., Sanchez-Rivera FJ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York., Pessina P; Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.; Department of Genetics, Harvard Medical School, Boston, Massachusetts., Kim JY; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts., Simoneau A; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts., Paschini M; Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.; Department of Genetics, Harvard Medical School, Boston, Massachusetts., Beytagh MC; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts., Stanclift CR; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Schenone M; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Mani DR; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Li C; Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts., Oh A; Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts., Li F; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York., Hu H; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York., Karatza A; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York., Bronson RT; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts., Shaw AT; Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts., Hata AN; Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts., Wong KK; Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York., Zou L; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts., Carr SA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Jacks T; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.; Howard Hughes Medical Institute, Cambridge, Massachusetts., Kim CF; Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts. carla.kim@childrens.harvard.edu.; Department of Genetics, Harvard Medical School, Boston, Massachusetts.; Harvard Stem Cell Institute, Cambridge, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Sep 15; Vol. 80 (18), pp. 3841-3854. Date of Electronic Publication: 2020 Jul 20.
DOI:	10.1158/0008-5472.CAN-20-1744
Abstrakt:	Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers (NSCLC). There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in BRG1 contribute to lung cancer progression. Using a combination of gain- and loss-of-function approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of replication stress responses. Single-molecule assessment of replication fork dynamics in BRG1-deficient cells revealed increased origin firing mediated by the prelicensing protein, CDC6. Quantitative mass spectrometry and coimmunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Finally, BRG1-deficient lung cancers were sensitive to pharmacologic inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their dependency on ATR can be leveraged therapeutically and potentially expanded to BRG1-mutant cancers in other tissues. SIGNIFICANCE: These findings indicate that inhibition of ATR is a promising therapy for the 10% of non-small cell lung cancer patients harboring mutations in SMARCA4/BRG1. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3841/F1.large.jpg. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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