A kinase-independent role for CDK8 in BCR-ABL1+ leukemia.
Nat Commun
; 10(1): 4741, 2019 10 18.
Article
em En
| MEDLINE
| ID: mdl-31628323
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leucemia-Linfoma Linfoblástico de Células Precursoras B
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Proteínas de Fusão bcr-abl
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Modelos Animais de Doenças
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Quinase 8 Dependente de Ciclina
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article