00085472can201744-sup-243971_2_supp_6420708_qd7514.png (860.66 kB)

Figure S2 from BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency

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posted on 2023-03-31, 03:42 authored by 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

Figure S2 shows proliferation, cell cycle, and replication fork related changes in human isogenic models of BRG1 loss.

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American Cancer Society

National Institute of General Medical Sciences

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ACS

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ARTICLE 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. 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.

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Keywords

Biomarkers Carcinogenesis DNA damage and repair Drug Targets Oncoprotein & tumor suppressor drug targets Gene Technologies High-throughput sequencing Lung Cancer Proteomics Small Molecule Agents Kinase inhibitors

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