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BRG1 loss predisposes lung cancers to replicative stress and ATR dependency

ABSTRACT: Gupta M, Concepcion CP, Fahey CG, Keshishian H, Bhutkar A, Brainson CF, Sanchez-Rivera FJ, Pessina P, Kim JY, Simoneau A, Paschini M, Beytagh MC, Stanclift C, Schenone M, Mani DR, Li C, Oh A, Li F, Hu H, Karatza A, Bronson RT, Shaw AT, Hata AN, Wong K, Zou L, Carr SA, Jacks T, Kim CF. Cancer Res 2020. Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers. 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 through pre-licensing protein CDC6. Quantitative mass spectrometry and co-immunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Lastly, we show that BRG1-deficient lung cancers are sensitive to the pharmacological inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their ATR dependency can be leveraged therapeutically, and potentially expanded to BRG1- mutant cancers in other tissues.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Steven A. Carr

PROVIDER: MSV000085701 | MassIVE | Wed Jul 08 11:17:00 BST 2020

REPOSITORIES: MassIVE

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