A kinase-independent role for CDK8 in BCR-ABL1 + leukemia

Nat Commun. 2019 Oct 18;10(1):4741. doi: 10.1038/s41467-019-12656-x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cyclin-Dependent Kinase 8 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 8 / genetics
  • Cyclin-Dependent Kinase 8 / metabolism*
  • Disease Models, Animal*
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Small Molecule Libraries / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • TOR Serine-Threonine Kinases
  • Fusion Proteins, bcr-abl
  • Cyclin-Dependent Kinase 8