1. BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency.
- Author
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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 CR, Schenone M, Mani DR, Li C, Oh A, Li F, Hu H, Karatza A, Bronson RT, Shaw AT, Hata AN, Wong KK, Zou L, Carr SA, Jacks T, and Kim CF
- Subjects
- Animals, Cell Cycle Proteins metabolism, Chromosomal Proteins, Non-Histone, DNA Helicases deficiency, Disease Progression, Female, Forkhead Transcription Factors, Gene Editing, Humans, Immunoprecipitation, Mass Spectrometry, Mice, Mice, Inbred C57BL, Mice, Nude, Nuclear Proteins deficiency, Nuclear Proteins metabolism, Sequence Analysis, RNA, Transcription Factors deficiency, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Carcinoma, Non-Small-Cell Lung genetics, DNA Helicases genetics, Gene Deletion, Lung Neoplasms genetics, Nuclear Proteins genetics, Transcription Factors genetics
- 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. SIGNIFICANCE: 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. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3841/F1.large.jpg., (©2020 American Association for Cancer Research.)
- Published
- 2020
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