Persistent Cdk2 inactivation drives growth arrest of BCR-ABL-expressing cells in response to dual inhibitor of SRC and ABL kinases SKI606

Leuk Res. 2007 Jul;31(7):979-87. doi: 10.1016/j.leukres.2006.09.022. Epub 2006 Nov 28.

Abstract

Complementary inhibition of tyrosine and SRC kinases implement dual SRC/ABL inhibitor effects in chronic myeloid leukemia (CML). Here, we show that one such inhibitor, SKI-606, induces persistent Cdk2 inactivation leading to growth arrest of BCR-ABL-expressing cells either IM-sensitive or driven to IM-resistance by other events than gene overexpression and point mutations. Inhibition of Akt serine/threonine kinase, a phosphatidylinositol 3 kinase (PI-3k) target that integrates p210 TK signaling with membrane-associated SRC kinases, is a central component of restored expression and subcellular redistribution of Cdk2 regulatory signals (p21 and p27 and Cdc25A phosphatase) in response to SKI-606. The putative roles of growth factor (namely IL-3) autocrine loop in BCR-ABL-expressing progenitor progression towards a drug-resistant phenotype are discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology*
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / pharmacology*
  • Fusion Proteins, bcr-abl
  • Humans
  • Interleukin-3 / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Nitriles / pharmacology*
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinolines / pharmacology*
  • Tumor Cells, Cultured / drug effects
  • cdc25 Phosphatases / metabolism
  • src-Family Kinases / antagonists & inhibitors*

Substances

  • Aniline Compounds
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Enzyme Inhibitors
  • Interleukin-3
  • Nitriles
  • Quinolines
  • Cyclin-Dependent Kinase Inhibitor p27
  • bosutinib
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • Proto-Oncogene Proteins c-abl
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • CDC25A protein, human
  • cdc25 Phosphatases