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SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer.
- Source :
-
Nature communications [Nat Commun] 2019 Feb 04; Vol. 10 (1), pp. 557. Date of Electronic Publication: 2019 Feb 04. - Publication Year :
- 2019
-
Abstract
- Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.
- Subjects :
- Animals
Carcinoma, Non-Small-Cell Lung genetics
Cell Survival genetics
Cell Survival physiology
Chromatin Immunoprecipitation
Cyclin-Dependent Kinase 4 genetics
Cyclin-Dependent Kinase 6 genetics
DNA Helicases genetics
Female
Humans
Immunohistochemistry
Lung Neoplasms genetics
Mice
Mice, SCID
Nuclear Proteins genetics
Transcription Factors genetics
Carcinoma, Non-Small-Cell Lung metabolism
Cyclin-Dependent Kinase 4 metabolism
Cyclin-Dependent Kinase 6 metabolism
DNA Helicases metabolism
Lung Neoplasms metabolism
Nuclear Proteins metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30718506
- Full Text :
- https://doi.org/10.1038/s41467-019-08380-1