Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells.
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.
University of Leicester, United Kingdom.
Cristian
C
Bellodi
Maria Rosa
MR
Lidonnici
Ashley
A
Hamilton
G Vignir
GV
Helgason
Angela Rachele
AR
Soliera
Mattia
M
Ronchetti
Sara
S
Galavotti
Kenneth W
KW
Young
Tommaso
T
Selmi
Rinat
R
Yacobi
Richard A
RA
Van Etten
Nick
N
Donato
Ann
A
Hunter
David
D
Dinsdale
Elena
E
Tirrò
Paolo
P
Vigneri
Pierluigi
P
Nicotera
Martin J
MJ
Dyer
Tessa
T
Holyoake
Paolo
P
Salomoni
Bruno
B
Calabretta
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use; D000069439:Dasatinib; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D051742:Transcription Factor CHOP / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; C497249:DDIT3 protein, human; C477012:MAP1LC3A protein, human; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D051742:Transcription Factor CHOP; D002738:Chloroquine; C040929:bafilomycin A1; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib; D002118:Calcium