A kinase-independent role for CDK8 in BCR-ABL1
Animals
Cell Line, Tumor
Cell Survival
/ drug effects
Cyclin-Dependent Kinase 8
/ antagonists & inhibitors
Disease Models, Animal
Fusion Proteins, bcr-abl
/ antagonists & inhibitors
Humans
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Mice, Transgenic
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
/ drug therapy
Protein Kinase Inhibitors
/ pharmacology
Signal Transduction
/ drug effects
Small Molecule Libraries
/ pharmacology
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 10 2019
18 10 2019
Historique:
received:
12
01
2019
accepted:
20
09
2019
entrez:
20
10
2019
pubmed:
20
10
2019
medline:
25
1
2020
Statut:
epublish
Résumé
Cyclin-dependent kinases (CDKs) are frequently deregulated in cancer and represent promising drug targets. We provide evidence that CDK8 has a key role in B-ALL. Loss of CDK8 in leukemia mouse models significantly enhances disease latency and prevents disease maintenance. Loss of CDK8 is associated with pronounced transcriptional changes, whereas inhibiting CDK8 kinase activity has minimal effects. Gene set enrichment analysis suggests that the mTOR signaling pathway is deregulated in CDK8-deficient cells and, accordingly, these cells are highly sensitive to mTOR inhibitors. Analysis of large cohorts of human ALL and AML patients reveals a significant correlation between the level of CDK8 and of mTOR pathway members. We have synthesized a small molecule YKL-06-101 that combines mTOR inhibition and degradation of CDK8, and induces cell death in human leukemic cells. We propose that simultaneous CDK8 degradation and mTOR inhibition might represent a potential therapeutic strategy for the treatment of ALL patients.
Identifiants
pubmed: 31628323
doi: 10.1038/s41467-019-12656-x
pii: 10.1038/s41467-019-12656-x
pmc: PMC6802219
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Small Molecule Libraries
0
Fusion Proteins, bcr-abl
EC 2.7.10.2
TOR Serine-Threonine Kinases
EC 2.7.11.1
Cyclin-Dependent Kinase 8
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4741Subventions
Organisme : Austrian Science Fund FWF
ID : P 27248
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : P 28571
Pays : Austria
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