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Cancer Res DOI:10.1158/0008-5472.CAN-20-1744

BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency.

Publication TypeJournal Article
Year of Publication2020
AuthorsGupta, M, Concepcion, CP, Fahey, CG, Keshishian, H, Bhutkar, A, Brainson, CF, Sánchez-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, K-K, Zou, L, Carr, SA, Jacks, T, Kim, CF
JournalCancer Res
Date Published2020 09 15
KeywordsAnimals, Ataxia Telangiectasia Mutated Proteins, Carcinoma, Non-Small-Cell Lung, Cell Cycle Proteins, Chromosomal Proteins, Non-Histone, Disease Progression, DNA Helicases, Female, Forkhead Transcription Factors, Gene Deletion, Gene Editing, Humans, Immunoprecipitation, Lung Neoplasms, Mass Spectrometry, Mice, Mice, Inbred C57BL, Mice, Nude, Nuclear Proteins, Sequence Analysis, RNA, Transcription Factors

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 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:


Alternate JournalCancer Res
PubMed ID32690724
PubMed Central IDPMC7501156
Grant ListEP-C-17-009 / EPA / EPA / United States
R01 CA216188 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
R01 CA237643 / CA / NCI NIH HHS / United States
U24 CA210979 / CA / NCI NIH HHS / United States
U01 CA214125 / CA / NCI NIH HHS / United States
U01 CA213333 / CA / NCI NIH HHS / United States
R01 CA205150 / CA / NCI NIH HHS / United States
U24 CA210986 / CA / NCI NIH HHS / United States
P20 GM121327 / GM / NIGMS NIH HHS / United States
P01 CA042063 / CA / NCI NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States