BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency
Year: 2020
Type: article
Abstract: 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.
Source: Cancer Research
Authors: Manav Gupta, Carla P. Concepcion, Caroline G. Fahey, Hasmik Keshishian, Arjun Bhutkar, Christine F. Brainson, Francisco J. Sanchez-Rivera, Patrizia Pessina, Jonathan Y. Kim, Antoine Simoneau, Margherita Paschini, Mary C. Beytagh, Caroline R. Stanclift, Monica Schenone, D.R. Mani, Chendi Li, Audris Oh, Fei Li, Hai Hu, Angeliki Karatza, Roderick T. Bronson, Alice T. Shaw, Aaron N. Hata, Kwok-Kin Wong, Lee Zou, Steven A. Carr, Tyler Jacks, Carla F. Kim
Institutions: Boston Children's Hospital, Harvard University, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, Broad Institute, University of Kentucky, Memorial Sloan Kettering Cancer Center, Massachusetts General Hospital, NYU Langone Health, NYU Langone’s Laura and Isaac Perlmutter Cancer Center, New York University, Howard Hughes Medical Institute, Harvard Stem Cell Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1058243294, Mechanisms of tumorigenesis in Brg1 mutant lung cancer, G1605188729, G1734642882, G2526390019, G2710633238, G532979230, Center of Excellence for High Throughput Proteogenomic Characterization, MICROSCALED PROTEOGENOMICS FOR CANCER CLINICAL TRIALS, Pre-Doctoral Training in Biological Sciences, G77253623, G8324081150, Integrated high throughput proteogenomic data analysis center for CPTAC, G8916889713, G9000178853, Cancer Center Support Grant, Cancer Center Support (Core) Grant, University of Kentucky Center for Cancer Metabolism, G941982536
OpenAlex ID: W3042861529