Imatinib and leptomycin B are effective in overcoming imatinib-resistance due to Bcr-Abl amplification and clonal evolution but not due to Bcr-Abl kinase domain mutation.
Treatment with imatinib is very effective in Bcr-Abl positive leukemia. However, development of resistance to this drug is a common phenomenon in late stage disease. The Bcr-Abl protein localizes to the cytoplasm in transformed cells but can enter the nucleus upon treatment with imatinib. Using leptomycin B, a nuclear export blocker, it has been shown that reactivated nuclear Bcr-Abl kinase activity can induce cell death, thus presenting an interesting potential treatment option for imatinib resistant disease. Here we show that the combination of imatinib and leptomycin B effectively induces cell death in imatinib-resistant Ba/F3 cells which display Bcr-Abl amplification or signs of clonal evolution. However, no such synergism is observed in imatinib-resistant Ba/F3 cells carrying the T315I mutation of Bcr-Abl or those which have lost Bcr-Abl expression. Thus, a partial inhibition of Bcr-Abl by imatinib is required for this approach in agreement with the proposed mode of action.
Kancha
Rama Krishna
RK
Dept. of Internal Medicine III, Technical University of Munich, Ismaningerstr. 22, 81675 Munich, Germany.
von Bubnoff
Nikolas
N
Miething
Cornelius
C
Peschel
Christian
C
Götze
Katharina S
KS
Duyster
Justus
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002892:Chromosomes, Human, Pair 22; D002899:Chromosomes, Human, Pair 9; D003114:Colony-Forming Units Assay; D004351:Drug Resistance / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl; D005784:Gene Amplification; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D009154:Mutation; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D001549:Benzamides; D005231:Fatty Acids, Unsaturated; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C038753:leptomycin B