BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency.
Cancer Res
; 80(18): 3841-3854, 2020 09 15.
Article
en En
| MEDLINE
| ID: mdl-32690724
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Proteínas Nucleares
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Eliminación de Gen
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Carcinoma de Pulmón de Células no Pequeñas
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ADN Helicasas
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Proteínas de la Ataxia Telangiectasia Mutada
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Neoplasias Pulmonares
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cancer Res
Año:
2020
Tipo del documento:
Article