BRG1 loss predisposes lung cancers to replicative stress and ATR dependency Journal Article
| Authors: | Gupta, M.; Concepcion, C. P.; Fahey, C. G.; Keshishian, H.; Bhutkar, A.; Brainson, C. F.; Sanchez-Rivera, F. J.; Pessina, P.; Kim, J. Y.; Simoneau, A.; Paschini, M.; Beytagh, M. C.; Stanclift, C. R.; Schenone, M.; Mani, D. R.; Li, C.; Oh, A.; Li, F.; Hu, H.; Karatza, A.; Bronson, R. T.; Shaw, A. T.; Hata, A. N.; Wong, K. K.; Zou, L.; Carr, S. A.; Jacks, T.; Kim, C. F. |
| Article Title: | BRG1 loss predisposes lung cancers to replicative stress and ATR dependency |
| 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. |
| Keywords: | protein; tumors; knockout; mutations; expression; complex; events; dna-replication; dormant origins; panther |
| Journal Title: | Cancer Research |
| Volume: | 80 |
| Issue: | 18 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-09-15 |
| Start Page: | 3841 |
| End Page: | 3854 |
| Language: | English |
| ACCESSION: | WOS:000572825500017 |
| DOI: | 10.1158/0008-5472.Can-20-1744 |
| PROVIDER: | wos |
| PMCID: | PMC7501156 |
| PUBMED: | 32690724 |
| Notes: | Article -- Source: Wos |
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