BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency

Cancer Res. 2020 Sep 15;80(18):3841-3854. doi: 10.1158/0008-5472.CAN-20-1744. Epub 2020 Jul 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Cell Cycle Proteins / metabolism
  • Chromosomal Proteins, Non-Histone
  • DNA Helicases / deficiency
  • DNA Helicases / genetics*
  • Disease Progression
  • Female
  • Forkhead Transcription Factors
  • Gene Deletion*
  • Gene Editing
  • Humans
  • Immunoprecipitation
  • Lung Neoplasms / genetics*
  • Mass Spectrometry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Sequence Analysis, RNA
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*

Substances

  • CDC6 protein, human
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Forkhead Transcription Factors
  • Nuclear Proteins
  • Transcription Factors
  • Whn protein
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • SMARCA4 protein, human
  • DNA Helicases