CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary.
Aminopyridines
/ therapeutic use
Animals
Benzimidazoles
/ therapeutic use
Carcinoma, Small Cell
/ drug therapy
Cell Line, Tumor
Cell Survival
/ drug effects
Chromatin Immunoprecipitation
Cyclin D1
/ deficiency
DNA Helicases
/ genetics
Female
Humans
Hypercalcemia
/ drug therapy
Mice
Mice, SCID
Nuclear Proteins
/ genetics
Ovarian Neoplasms
/ drug therapy
Piperazines
/ therapeutic use
Protein Kinase Inhibitors
/ therapeutic use
Purines
/ therapeutic use
Pyridines
/ therapeutic use
RNA, Small Interfering
/ 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:
04
10
2018
entrez:
6
2
2019
pubmed:
6
2
2019
medline:
11
4
2019
Statut:
epublish
Résumé
Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16
Identifiants
pubmed: 30718512
doi: 10.1038/s41467-018-06958-9
pii: 10.1038/s41467-018-06958-9
pmc: PMC6361890
doi:
Substances chimiques
Aminopyridines
0
Benzimidazoles
0
Nuclear Proteins
0
Piperazines
0
Protein Kinase Inhibitors
0
Purines
0
Pyridines
0
RNA, Small Interfering
0
Transcription Factors
0
Cyclin D1
136601-57-5
abemaciclib
60UAB198HK
SMARCA4 protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
palbociclib
G9ZF61LE7G
ribociclib
TK8ERE8P56
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
558Subventions
Organisme : DOD | Congressionally Directed Medical Research Programs (CDMRP)
ID : W81XWH-15-1-0497
Pays : International
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
ID : MOP-130540
Pays : International
Organisme : Canadian HIV Trials Network, Canadian Institutes of Health Research (Réseau canadien pour les essais VIH des IRSC)
ID : PJT-156233
Pays : International
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