Inhibition of autophagy: a new strategy to enhance sensitivity of chronic myeloid leukemia stem cells to tyrosine kinase inhibitors.
Imatinib mesylate (IM) has become standard therapy for patients with chronic myeloid leukemia (CML), but CML stem cells are intrinsically resistant to IM and to second/third-generation tyrosine kinase inhibitors (TKIs), allowing the persistence of a 'reservoir' of BCR-ABL-expressing CML-initiating cells potentially responsible for disease progression. Although it is still controversial whether the 'insensitivity' of CML stem cells to treatment with TKIs is due to BCR-ABL-dependent or independent mechanisms, recent evidence indicates that treatment with IM suppresses BCR-ABL-dependent signaling in CML stem cells with no adverse effects on their survival. Treatment of CML cells with IM/TKIs induces autophagy, a genetically regulated process of adaptation to metabolic stress which may allow tumor cells to become metabolically inert, enabling their survival under conditions that may mimic growth factor/nutrient deprivation. Based on this hypothesis, TKI-induced autophagy may 'antagonize' TKI-induced cell death and inhibition of autophagy may eliminate this survival mechanism by restoring 'sensitivity' of CML stem cells to treatment with IM/TKIs. Consistent with this, recent evidence indicates that phenotypically and functionally defined CML-enriched stem cells that are insensitive to treatment with TKIs are efficiently eliminated by the combination of TKI and chloroquine, an inhibitor of late stage autophagy. Thus, inhibition of autophagy may 'sensitize' CML stem cells to treatment with TKIs, thus preserving the high specificity of TKI-based therapies.
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. B_Calabretta@mail.jci.tju.edu
Bruno
B
Calabretta
Paolo
P
Salomoni
D001343:Autophagy / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*
D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl
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