Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro

H G Jorgensen, E K Allan, S M Graham, J L Godden, L Richmond, M A Elliott, J C Mountford, C J Eaves, T L Holyoake

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Abstract

Recent studies indicate that a rare population of primitive quiescent BCR-ABL(+) cells are innately insensitive to imatinib mesylate (IM) and persist after IM therapy of patients with chronic myeloid leukemia (CML). New approaches to the eradication of these cells are therefore likely to be crucial to the development of curative therapies for CML. We have now found that Ara-C, LY294002 (a PI-3 ( phosphatidylinositol-3' kinase) kinase inhibitor), 17AAG (a heat-shock protein (HSP)-90 antagonist) and lonafarnib (a farnesyltransfease inhibitor) all enhance the toxicity of IM on K562 cells and on the total CD34(+) leukemic cell population from chronic phase CML patients. However, for quiescent CD34(+) leukemic cells, this was achieved only by concomitant exposure of the cells to lonafarnib. Ara-C or LY294002 alone blocked the proliferation of these cells but did not kill them, and Ara-C, LY294002 or 17AAG in combination with IM enhanced the cytostatic effect of IM but did not prevent the subsequent regrowth of the surviving leukemic cells. These studies demonstrate the importance of in vitro testing of novel agents on the subset of primary leukemic cells most likely to determine long- term treatment outcomes in vivo.

Original languageEnglish
Pages (from-to)1184-1191
Number of pages8
JournalLeukemia
Volume19
Issue number7
DOIs
Publication statusPublished - Jul 2005

Keywords

  • CML
  • imatinib
  • stem cells
  • chronic myeloid-leukemia
  • chronic myelogenous leukemia
  • tyrosine kinase inhibitor
  • complete cytogenetic remission
  • low-dose cytarabine
  • clinical resistance
  • hematopoietic progenitors
  • chemotherapeutic drugs
  • multidrug-resistance
  • antileukemic agents

Cite this

Jorgensen, H. G., Allan, E. K., Graham, S. M., Godden, J. L., Richmond, L., Elliott, M. A., Mountford, J. C., Eaves, C. J., & Holyoake, T. L. (2005). Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro. Leukemia, 19(7), 1184-1191. https://doi.org/10.1038/sj.leu.2403785