Zeitschriftenaufsatz
|
2019
A kinase-independent role for CDK8 in BCR-ABL1+ leukemia
Autor:in
Menzl, Ingeborg; Zhang, Ting; Berger-Becvar, Angelika; Grausenburger, Reinhard; heller, gerwin; Prchal-Murphy, Michaela; Edlinger, L.; Knab, Vanessa M.; Uras, Iris; Grundschober, Eva; Bauer, K.; Roth, Mareike; Skucha, A.; Liu, Yao; Hatcher, John M.; Liang, Yanke; Kwiatkowski, Nicholas; Fuxl, Daniela; Hoelbl-Kovacic, Andrea; Kubicek, Stefan; Melo, Junia; Valent, Peter; Weichhart, Thomas; Grebien, Florian; Zuber, Johannes; Gray, Nathanael S.; Sexl, Veronika
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
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.
Schlagwörter
Animals; Cell Line, Tumor; Cell Survivaldrug effectsgenetics; Cyclin-Dependent Kinase 8antagonists & inhibitorsgeneticsmetabolism; Disease Models, Animal; Fusion Proteins, bcr-ablantagonists & inhibitorsgeneticsmetabolism; Humans; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; Precursor B-Cell Lymphoblastic Leukemia-Lymphomadrug therapygeneticsmetabolism; Protein Kinase Inhibitorspharmacology; Signal Transductiondrug effectsgenetics; Small Molecule Librariespharmacology; TOR Serine-Threonine Kinasesantagonists & inhibitorsgeneticsmetabolism
Dokumententyp
Originalarbeit
CC Lizenz
CCBY
Open Access Type
Gold
ISSN/eISSN
2041-1723 -
10.1038/s41467-019-12656-x
WoS ID
PubMed ID