BRD4-mediated repression of p53 is a target for combination therapy in AML.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Blast Crisis
/ pathology
Cell Cycle Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Disease Models, Animal
Gene Expression Regulation, Leukemic
/ drug effects
Humans
Intracellular Signaling Peptides and Proteins
/ metabolism
Leukemia, Myeloid, Acute
/ drug therapy
Mice
Molecular Targeted Therapy
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2
/ antagonists & inhibitors
RNA, Messenger
/ genetics
Transcription Factors
/ antagonists & inhibitors
Tumor Suppressor Protein p53
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 01 2021
11 01 2021
Historique:
received:
18
10
2019
accepted:
25
11
2020
entrez:
12
1
2021
pubmed:
13
1
2021
medline:
22
1
2021
Statut:
epublish
Résumé
Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53, encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate wild-type p53, and BET inhibitors (BETi), targeting the BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report enhanced toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETi's ability to evict an unexpected repressive form of BRD4 from p53 target genes, and hence potentiate MDM2i-induced p53 activation. These results indicate that wild-type TP53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.
Identifiants
pubmed: 33431824
doi: 10.1038/s41467-020-20378-8
pii: 10.1038/s41467-020-20378-8
pmc: PMC7801601
doi:
Substances chimiques
BRD4 protein, human
0
Cell Cycle Proteins
0
Intracellular Signaling Peptides and Proteins
0
RNA, Messenger
0
Transcription Factors
0
Tumor Suppressor Protein p53
0
tribbles 2 protein, mouse
0
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
241Subventions
Organisme : Cancer Research UK
ID : A17196
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Chief Scientist Office
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 105641/Z/14/Z
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA030199
Pays : United States
Organisme : Cancer Research UK
ID : C10652/A16566
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A25142
Pays : United Kingdom
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