BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency
Name
nihms-1613876.pdf
Description
Accepted version
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2.51 MB
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Unknown
Checksum (MD5)
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Author(s)
Gupta, Manav
Concepcion, Carla P.
Fahey, Caroline G.
Keshishian, Hasmik
Bhutkar, Arjun
Brainson, Christine F.
Sanchez-Rivera, Francisco J.
Pessina, Patrizia
Kim, Jonathan Y.
Simoneau, Antoine
Date Issued
July 2020
Journal
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Version
Author's final manuscript
Abstract
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
Howard Hughes Medical Institute
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1158/0008-5472.can-20-1744
