Suppression of autophagy by BCR/ABL.
Imatinib and second generation BCR/ABL tyrosine kinase inhibitors (TKIs) serve now as standard therapies for patients with chronic myelogenous leukemia (CML); however, CML stem cells are intrinsically insensitive to the cell death-inducing effects of TKIs, allowing the persistence of a "reservoir" of BCR/ABL-expressing CML-initiating cells potentially responsible for disease relapse and progression. Although it is still controversial whether the "insensitivity" of CML stem cells to treatment with TKI is due to BCR/ABL-dependent or independent mechanisms, treatment with IM appears to suppress BCR/ABL-dependent signaling in CML stem cells with no adverse effects on their survival. Recent evidence indicates that BCR/ABL suppresses and treatment of CML cells with IM/TKIs induces autophagy, a genetically-regulated process of adaptation to metabolic stress which could allow tumor cells to become metabolically inert enabling their survival under conditions that may mimic growth factor/nutrients 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/TKI. Consistent with this, phenotypically and functionally defined CML-enriched stem cells insensitive to treatment with TKI are efficiently eliminated by the combination of TKI and chloroquine, an inhibitor of late stage autophagy. Thus, inhibition of autophagy may improve the potent and specific effects of TKIs by rendering CML stem cells sensitive to these targeted therapies.
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. B_Calabretta@mail.jci.tju.edu
Bruno
B
Calabretta
Paolo
P
Salomoni
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D002738:Chloroquine / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D002738:Chloroquine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl