Combined Targeting of the BRD4-NUT-p300 Axis in NUT Midline Carcinoma by Dual Selective Bromodomain Inhibitor, NEO2734.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Benzimidazoles
/ pharmacology
Biomarkers, Tumor
Carcinoma
/ drug therapy
Cell Cycle
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Proliferation
E1A-Associated p300 Protein
/ antagonists & inhibitors
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasm Proteins
/ antagonists & inhibitors
Nuclear Proteins
/ antagonists & inhibitors
Pyridones
/ pharmacology
Transcription Factors
/ antagonists & inhibitors
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
03
02
2020
revised:
12
03
2020
accepted:
13
04
2020
pubmed:
7
5
2020
medline:
3
6
2021
entrez:
7
5
2020
Statut:
ppublish
Résumé
NUT midline carcinoma (NMC) is a rare, aggressive subtype of squamous carcinoma that is driven by the BRD4-NUT fusion oncoprotein. BRD4, a BET protein, binds to chromatin through its two bromodomains, and NUT recruits the p300 histone acetyltransferse (HAT) to activate transcription of oncogenic target genes. BET-selective bromodomain inhibitors have demonstrated on-target activity in patients with NMC, but with limited efficacy. P300, like BRD4, contains a bromodomain. We show that combining selective p300/CBP and BET bromodomain inhibitors, GNE-781 and OTX015, respectively, induces cooperative depletion of MYC and synergistic inhibition of NMC growth. Treatment of NMC cells with the novel dual p300/CBP and BET bromodomain-selective inhibitor, NEO2734, potently inhibits growth and induces differentiation of NMC cells
Identifiants
pubmed: 32371576
pii: 1535-7163.MCT-20-0087
doi: 10.1158/1535-7163.MCT-20-0087
doi:
Substances chimiques
Antineoplastic Agents
0
BRD4 protein, human
0
Benzimidazoles
0
Biomarkers, Tumor
0
Cell Cycle Proteins
0
NEO2734
0
NUTM1 protein, human
0
Neoplasm Proteins
0
Nuclear Proteins
0
Pyridones
0
Transcription Factors
0
E1A-Associated p300 Protein
EC 2.3.1.48
EP300 protein, human
EC 2.3.1.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1406-1414Subventions
Organisme : NCI NIH HHS
ID : R01 CA124633
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM062437
Pays : United States
Organisme : NIGMS NIH HHS
ID : K99 GM124357
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006516
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.