BRG1 loss predisposes lung cancers to replicative stress and ATR dependency

Manav Gupta, Carla P. Concepcion, Caroline G. Fahey, Hasmik Keshishian, Arjun Bhutkar, Christine F. Brainson, Francisco J. Sanchez-Rivera, Patrizia Pessina, Jonathan Y. Kim, Antoine Simoneau, Margherita Paschini, Mary C. Beytagh, Caroline R. Stanclift, Monica Schenone, D. R. Mani, Chendi Li, Audris Oh, Fei Li, Hai Hu, Angeliki KaratzaRoderick T. Bronson, Alice T. Shaw, Aaron N. Hata, Kwok Kin Wong, Lee Zou, Steven A. Carr, Tyler Jacks, Carla F. Kim

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish
Pages (from-to)3841-3854
Number of pages14
JournalCancer Research
Volume80
Issue number18
DOIs
StatePublished - 15 Sep 2020
Externally publishedYes

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