Development of Resistance to Dasatinib in Bcr/Abl-positive Acute Lymphoblastic Leukemia

Leukemia. 2010 Apr;24(4):813-20. doi: 10.1038/leu.2009.302. Epub 2010 Jan 28.

Abstract

Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Philadelphia chromosome-positive (Ph-positive) leukemias. At a once-daily dose and a relatively short half-life of 3-5 h, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell-surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low-dose dasatinib monotherapy will be effective in causing irreversible apoptosis in Ph-positive ALL, but suggest that combined treatment with dasatinib and drugs such as AMD3100 may be effective.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Cells, Cultured
  • Dasatinib
  • Drug Resistance, Neoplasm*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Leukemia, Experimental / drug therapy*
  • Leukemia, Experimental / metabolism
  • Leukemia, Experimental / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Phosphorylation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism*
  • Pyrimidines / pharmacology*
  • Receptors, CXCR4 / metabolism
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Stromal Cells / radiation effects
  • Thiazoles / pharmacology*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism

Substances

  • CXCR4 protein, mouse
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Receptors, CXCR4
  • Thiazoles
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • src-Family Kinases
  • Dasatinib