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

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.

• Authors: Manuela Mancini, Gianluca Brusa, Elisa Zuffa, Patrizia Corrado, Giovanni Martinelli, Tiziana Grafone, Enza Barbieri, Maria Alessandra Santucci
• Journal: Leukemia research (Leuk Res) Vol. 31 Issue 7 Pg. 979-87 (Jul 2007) ISSN: 0145-2126 [Print] England
• PMID: 17129604 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Aniline Compounds (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cyclin-Dependent Kinase 2 (antagonists & inhibitors, 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, 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)