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.
|Number of pages||14|
|State||Published - Sep 15 2020|
Bibliographical noteFunding Information:
C.P. Concepcion reports funding from American Cancer Society (postdoctoral fellowship) and Koch Institute (Quinquennial postdoctoral fellowship) during the conduct of the study. C.R. Stanclift reports grants from NCI Clinical Proteomic Tumor Analysis Consortium grants NIH/NCI U24-CA210986 during the conduct of the study. D.R. Mani reports grants from NCI (CPTAC #U24-CA210979) during the conduct of the study. A.T. Shaw reports personal fees from Novartis (employment, equity) outside the submitted work. A.N. Hata reports grants from Amgen, Pfizer, Relay Therapeutics, Roche/Genentech, Eli Lilly, Blueprint Therapeutics, and Novartis outside the submitted work. K.-K. Wong is an equity holder at G1 Therapeutics, Zentalis Therapeutics, and Epiphanies Therapeutics outside the submitted work. S.A. Carr reports grants from NIH/NCI during the conduct of the study, personal fees from Kymera and PTM Biolab, and Biogen (outside the submitted work), and nonfinancial support from Seer outside the submitted work. T. Jacks is a member of the board of directors of Amgen and Thermo Fisher Scientific, a co-founder of Dragonfly Therapeutics and T2 Biosystems, serves on the scientific advisory board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics; none of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this article. T. Jacks also reports receiving funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research (outside the submitted work). C.F. Kim reports grants from NIH R01CA216188-01A1 (for project entitled “Mechanisms of Tumorigenesis in Brg1 Mutant Lung Cancer”), American Cancer Society Mission Boost Grant for project entitled “Precision Therapy for SMARCA4-Mutant Lung Cancer,” reports consortium associations with Longfonds Stichting and Celgene Corporation, and reports receiving funds from Genentech Inc., The Rockefeller University, and American Thoracic Society. No potential conflicts of interest were disclosed by the other authors.
We would like to thank members of the Kim Lab, Raul Mostoslavsky, Cigall Kadoch, Peter Sicinski, and Lynette Scholl for helpful discussions. M. Gupta was supported by the Albert J. Ryan graduate fellowship. C.P. Concepcion was supported by the American Cancer Society (ACS) postdoctoral fellowship 130361-PF-17-009-01-CDD and the Koch Institute (KI) Quinquennial Postdoctoral Fellowship. C.F. Brainson was supported by grants from the National Institute of General Medical Sciences P20-GM121327-03, NCI R01-CA237643, and the ACS Research Scholar Grant 133123-RSG-19-081-01-TBG. Mass spectrometry/analysis was performed at the Broad Institute and was supported, in part, by grants from the NCI Clinical Proteomic Tumor Analysis Consortium grants NIH/NCI U24-CA210986 and NIH/ NCI U01-CA214125 (to S.A. Carr) and NIH/NCI U24-CA210979 (to D.R. Mani). K.-K. Wong was funded by NCI R01-CA216188, R01-CA205150, and U01-CA213333. T. Jacks was supported by grants from Howard Hughes Medical Institute, Ludwig Center for Molecular Oncology at MIT, NIH P01 Jacks P01-CA42063, The Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center (DF/HCC), and grants from the NCI KI Cancer Center Support Grant P30-CA14051. C.F. Kim was supported by NIH/NCI R01-CA216188, ACS Mission Boost Grant 71647, and DF/HCC Bridge Grant 72387.
We would like to thank members of the Kim Lab, Raul Mostoslavsky, Cigall Kadoch, Peter Sicinski, and Lynette Scholl for helpful discussions. M. Gupta was supported by the Albert J. Ryan graduate fellowship. C.P. Concepcion was supported by the American Cancer Society (ACS) postdoctoral fellowship 130361-PF-17-009-01-CDD and the Koch Institute (KI) Quinquennial Postdoctoral Fellowship. C.F. Brainson was supported by grants from the National Institute of General Medical Sciences P20-GM121327-03, NCI R01-CA237643, and the ACS Research Scholar
© 2020 American Association for Cancer Research.
ASJC Scopus subject areas
- Cancer Research