Targeting autophagy potentiates tyrosine kinase inhibitor–induced cell death in Philadelphia chromosome–positive cells, including primary CML stem cells

Bellodi, C. et al. (2009) Targeting autophagy potentiates tyrosine kinase inhibitor–induced cell death in Philadelphia chromosome–positive cells, including primary CML stem cells. Journal of Clinical Investigation, 119(5), pp. 1109-1123. (doi: 10.1172/JCI35660)

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Publisher's URL: http://dx.doi.org/10.1172/JCI35660

Abstract

Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Hamilton, Ms Ashley and Helgason, Dr Vignir
Authors: Bellodi, C., Lidonnici, M. R., Hamilton, A., Helgason, G. V., Soliera, A. R., Ronchetti, M., Galavotti, S., Young, K. W., Selmi, T., Yacobi, R., Van Etten, R. A., Donato, N., Hunter, A., Dinsdale, D., Tirrò, E., Vigneri, P., Nicotera, P., Dyer, M. J., Holyoake, T., Salomoni, P., and Calabretta, B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
ISSN:0021-9738
ISSN (Online):1558-8238
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