Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification

Int J Cancer. 2008 Jun 1;122(11):2621-7. doi: 10.1002/ijc.23435.

Abstract

Because imatinib (IM) resistance in chronic myeloid leukemia is primarily caused by the re-establishment of Abl kinase, new inhibitors may be efficacious. We evaluated 3 new agents against 2 new K562 variants, IM-R1 and IM-R2 cells, which were developed having 7- and 27-fold greater IM resistance, respectively, than the parental K562 cells. Both variants possessed BCR-ABL gene amplification along with elevated levels of its transcript and protein. Greater BCR-ABL gene amplification was observed in IM-R2 cells than in IM-R1 cells, which was consistent with the higher mRNA and protein levels of Bcr-Abl, and ultimately correlated with the greater IM resistance in IM-R2 cells. No mutation in the Abl kinase domain was detected in either variant. Despite the absence of Lyn overexpression, the Src kinase inhibitor CGP76030 showed positive cooperability with IM in inhibiting cell growth of not only K562 cells but also these 2 variants. This might be because of the augmented inhibition of Erk1/2 phosphorylation. The new Abl kinase inhibitor nilotinib was 10-fold more potent than IM in inhibiting the growth of K562 cells. Nilotinib inhibited the growth of IM-R1 and IM-R2 cells as potently as K562 cells. The combination of nilotinib with CGP76030 showed little additivity, because the potency of nilotinib masked the efficacy of CGP76030. The new dual Abl/Lyn inhibitor INNO-406 (formerly NS-187) was slightly more potent than nilotinib in inhibiting the growth of all 3 cell lines. Because BCR-ABL gene amplification occurs in blast crisis, these inhibitors might overcome IM resistance in such patients' leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / isolation & purification
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzamides
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm*
  • Flow Cytometry
  • Fusion Proteins, bcr-abl / genetics*
  • Gene Amplification*
  • Genes, abl*
  • Humans
  • Imatinib Mesylate
  • In Situ Hybridization, Fluorescence
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Mutation
  • Phosphorylation
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • Pyrroles / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • src-Family Kinases / antagonists & inhibitors

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Benzamides
  • CGP 76030
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • abl-bcr fusion protein, human
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • bafetinib