Synergism between bosutinib (SKI-606) and the Chk1 inhibitor (PF-00477736) in highly imatinib-resistant BCR/ABL⁺ leukemia cells

Leuk Res. 2015 Jan;39(1):65-71. doi: 10.1016/j.leukres.2014.10.009. Epub 2014 Nov 11.

Abstract

Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL(+) leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph(+) ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34(+) CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34(+) cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph(+) ALL.

Keywords: BCR/ABL; Bosutinib; Chk1 inhibitor; Chronic myeloid leukemia.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Aniline Compounds* / agonists
  • Aniline Compounds* / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Benzamides*
  • Benzodiazepinones* / agonists
  • Benzodiazepinones* / pharmacology
  • Checkpoint Kinase 1
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mutation, Missense
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitriles* / agonists
  • Nitriles* / pharmacology
  • Piperazines*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Kinase Inhibitors*
  • Protein Kinases / metabolism*
  • Pyrazoles* / agonists
  • Pyrazoles* / pharmacology
  • Pyrimidines*
  • Quinolines* / agonists
  • Quinolines* / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • Benzamides
  • Benzodiazepinones
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitriles
  • PF 00477736
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Quinolines
  • bosutinib
  • Imatinib Mesylate
  • Protein Kinases
  • Fusion Proteins, bcr-abl
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human