BRG1 Loss Predisposes Lung Cancers to Replicative Stress and ATR Dependency.

Cancer Research
Manav GuptaCarla F Kim

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. GRAPH...Continue Reading

References

Sep 30, 1994·Science·A BensimonD Bensimon
Jun 5, 2002·Annual Review of Biochemistry·Stephen P Bell, Anindya Dutta
Sep 4, 2003·Genome Research·Paul D ThomasApurva Narechania
Feb 26, 2004·The Journal of Biological Chemistry·Catherine J MerrickJohn F X Diffley
Sep 24, 2004·Current Biology : CB·John F X Diffley
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Nov 17, 2005·Cancer Research·Erica L JacksonTyler Jacks
Apr 5, 2008·Human Mutation·Pedro P MedinaMontse Sanchez-Cespedes
May 17, 2008·Cancer Research·Selina GlarosDavid Reisman
Jan 30, 2009·Carcinogenesis·Salvador Rodriguez-Nieto, Montse Sanchez-Cespedes
Mar 6, 2009·Genome Biology·Ben LangmeadSteven L Salzberg
Oct 29, 2010·Genome Biology·Simon Anders, Wolfgang Huber
Nov 26, 2010·Bioorganic & Medicinal Chemistry Letters·Marc LabroliTimothy J Guzi
Nov 26, 2010·Bioorganic & Medicinal Chemistry Letters·Michael P DwyerTimothy J Guzi
Nov 26, 2010·Proceedings of the National Academy of Sciences of the United States of America·Christine M FillmoreCharlotte Kuperwasser
Feb 1, 2011·Human Mutation·Salvador Rodriguez-NietoMontse Sanchez-Cespedes
Jun 10, 2011·Nature Reviews. Cancer·Boris G Wilson, Charles W M Roberts
Feb 23, 2013·Bioinformatics·Ning LengChristina Kendziorski
Apr 4, 2013·Science Signaling·Jianjiong GaoNikolaus Schultz
May 24, 2013·Nature·Emily C DykhuizenGerald R Crabtree
Jul 12, 2013·American Journal of Respiratory and Critical Care Medicine·Stephanie Cardarella, Bruce E Johnson
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
Dec 18, 2013·Science·Ophir ShalemFeng Zhang
Mar 25, 2014·Nature Genetics·Petar JelinicDouglas A Levine
Aug 1, 2014·Nature·UNKNOWN Cancer Genome Atlas Research Network
Oct 23, 2014·Nature·Francisco J Sánchez-RiveraTyler Jacks
Apr 25, 2015·Nature Reviews. Cancer·Hélène GaillardAndrés Aguilera
Oct 12, 2015·DNA Repair·Gina KavanaughDavid Cortez
Nov 21, 2015·Cancer Discovery·Nadya DimitrovaTyler Jacks
Jan 16, 2016·Cell Systems·Arthur LiberzonPablo Tamayo
Apr 23, 2016·Methods : a Companion to Methods in Enzymology·Jadwiga NieminuszczyWojciech Niedzwiedz
Sep 13, 2016·Annual Review of Genetics·Stephanie A Yazinski, Lee Zou
Dec 14, 2016·Nature Communications·Chris T WilliamsonChristopher J Lord

❮ Previous
Next ❯

Citations

Oct 28, 2020·Molecular Oncology·Liang LiuWei Zhang
Apr 24, 2021·Cancer Research·Roman M ChabanonSophie Postel-Vinay
Apr 13, 2021·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Joao V AlessiMark M Awad
Jul 31, 2021·Current Opinion in Genetics & Development·Antoine Simoneau, Lee Zou
Sep 23, 2021·Experimental & Molecular Medicine·Seo Yun LeeKyle M Miller

❮ Previous
Next ❯

Related Concepts

Related Feeds

Ataxia telangiectasia (MDS)

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.

Ataxia telangiectasia

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.