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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Maria Rosa Lidonnici
  • Ashley Hamilton
  • G Vignir Helgason
  • Angela Rachele Soliera
  • Mattia Ronchetti
  • Sara Galavotti
  • Kenneth W Young
  • Tommaso Selmi
  • Rinat Yacobi
  • Richard A Van Etten
  • Nick Donato
  • Ann Hunter
  • David Dinsdale
  • Elena Tirrò
  • Paolo Vigneri
  • Pierluigi Nicotera
  • Martin J Dyer
  • Tessa Holyoake
  • Paolo Salomoni
  • Bruno Calabretta
External organisations
  • University of Leicester
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology

Keywords

  • Animals, Antineoplastic Agents, Autophagy, Benzamides, Calcium, Cell Death, Cell Line, Tumor, Chloroquine, Dasatinib, Endoplasmic Reticulum, Fusion Proteins, bcr-abl, Gene Expression, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Macrolides, Mice, Mice, Inbred C3H, Microtubule-Associated Proteins, Neoplastic Stem Cells, Piperazines, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Pyrimidines, RNA Interference, Thiazoles, Transcription Factor CHOP, Xenograft Model Antitumor Assays
Original languageEnglish
Pages (from-to)1109-23
Number of pages15
JournalJournal of Clinical Investigation
Volume119
Issue number5
Publication statusPublished - 2009 May
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes