Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma

Oncotarget. 2015 Oct 6;6(30):30149-64. doi: 10.18632/oncotarget.4999.


Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphomas (ALK+ ALCL) occur predominantly in children and young adults. Their treatment, based on aggressive chemotherapy, is not optimal since ALCL patients can still expect a 30% 2-year relapse rate. Tumor relapses are very aggressive and their underlying mechanisms are unknown. Crizotinib is the most advanced ALK tyrosine kinase inhibitor and is already used in clinics to treat ALK-associated cancers. However, crizotinib escape mechanisms have emerged, thus preventing its use in frontline ALCL therapy. The process of autophagy has been proposed as the next target for elimination of the resistance to tyrosine kinase inhibitors. In this study, we investigated whether autophagy is activated in ALCL cells submitted to ALK inactivation (using crizotinib or ALK-targeting siRNA). Classical autophagy read-outs such as autophagosome visualization/quantification by electron microscopy and LC3-B marker turn-over assays were used to demonstrate autophagy induction and flux activation upon ALK inactivation. This was demonstrated to have a cytoprotective role on cell viability and clonogenic assays following combined ALK and autophagy inhibition. Altogether, our results suggest that co-treatment with crizotinib and chloroquine (two drugs already used in clinics) could be beneficial for ALK-positive ALCL patients.

Keywords: NPM-ALK; anaplastic large cell lymphoma; autophagy; crizotinib; cytoprotection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Autophagy / drug effects*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chloroquine / pharmacology*
  • Crizotinib
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / drug therapy*
  • Lymphoma, Large-Cell, Anaplastic / enzymology
  • Lymphoma, Large-Cell, Anaplastic / genetics
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Mice, Inbred NOD
  • Mice, SCID
  • Microtubule-Associated Proteins / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • RNA Interference
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / drug effects
  • Time Factors
  • Transfection
  • Xenograft Model Antitumor Assays


  • MAP1LC3B protein, human
  • Microtubule-Associated Proteins
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • Chloroquine
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases