Details

Autor(en) / Beteiligte

• Gupta, Manav
• Concepcion, Carla P
• Fahey, Caroline G
• Keshishian, Hasmik
• Bhutkar, Arjun
• Brainson, Christine F
• Sanchez-Rivera, Francisco J
• Pessina, Patrizia
• Kim, Jonathan Y
• Simoneau, Antoine
• Paschini, Margherita
• Beytagh, Mary C
• Stanclift, Caroline R
• Schenone, Monica
• Mani, D R
• Li, Chendi
• Oh, Audris
• Li, Fei
• Hu, Hai
• Karatza, Angeliki
• Bronson, Roderick T
• Shaw, Alice T
• Hata, Aaron N
• Wong, Kwok-Kin
• Zou, Lee
• Carr, Steven A
• Jacks, Tyler
• Kim, Carla F

Titel

BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency

Ist Teil von

• Cancer research (Chicago, Ill.), 2020-09, Vol.80 (18), p.3841-3854

Ort / Verlag

United States

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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: http://cancerres.aacrjournals.org/content/canres/80/18/3841/F1.large.jpg.