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BRG1 loss predisposes lung cancers to replicative stress and ATR dependency
Name
nihms-1613876.pdf
Description
Accepted version
Size
2.51 MB
Format
Adobe PDF
Checksum (MD5)
8593e276551d9533e49b882984778fa8
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
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.
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
10.1158/0008-5472.CAN-20-1744
