SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer.
Animals
Carcinoma, Non-Small-Cell Lung
/ genetics
Cell Survival
/ genetics
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
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 02 2019
04 02 2019
Historique:
received:
24
04
2018
accepted:
03
01
2019
entrez:
6
2
2019
pubmed:
6
2
2019
medline:
11
4
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30718506
doi: 10.1038/s41467-019-08380-1
pii: 10.1038/s41467-019-08380-1
pmc: PMC6362083
doi:
Substances chimiques
Nuclear Proteins
0
Transcription Factors
0
CDK4 protein, human
EC 2.7.11.22
CDK6 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
SMARCA4 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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