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- Manav Gupta
- 1Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.
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- Carla P. Concepcion
- 4David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
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- Caroline G. Fahey
- 1Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.
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- Hasmik Keshishian
- 6Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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- Arjun Bhutkar
- 4David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
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- Christine F. Brainson
- 7Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
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- Francisco J. Sanchez-Rivera
- 9Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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- Patrizia Pessina
- 1Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.
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- Jonathan Y. Kim
- 4David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
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- Antoine Simoneau
- 10Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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- Margherita Paschini
- 1Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.
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- Mary C. Beytagh
- 4David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
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- Caroline R. Stanclift
- 6Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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- Monica Schenone
- 6Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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- D.R. Mani
- 6Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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- Chendi Li
- 12Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts.
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- Audris Oh
- 12Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts.
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- Fei Li
- 13Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.
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- Hai Hu
- 13Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.
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- Angeliki Karatza
- 13Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.
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- Roderick T. Bronson
- 14Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.
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- Alice T. Shaw
- 12Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts.
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- Aaron N. Hata
- 12Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital Harvard Medical School, Boston, Massachusetts.
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- Kwok-Kin Wong
- 13Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.
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- Lee Zou
- 10Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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- Steven A. Carr
- 6Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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- Tyler Jacks
- 4David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
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- Carla F. Kim
- 1Stem Cell Program, Division of Hematology/Oncology and Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts.
説明
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>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.</jats:p> </jats:sec>
収録刊行物
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- Cancer Research
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Cancer Research 80 (18), 3841-3854, 2020-09-15
American Association for Cancer Research (AACR)