Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma.
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.
Inserm, UMR1037 CRCT, F-31000 Toulouse, France.|Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.|CNRS, ERL5294 CRCT, F-31000 Toulouse, France.
Géraldine
G
Mitou
Inserm, UMR1037 CRCT, F-31000 Toulouse, France.|Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.|CNRS, ERL5294 CRCT, F-31000 Toulouse, France.
Julie
J
Frentzel
Phenotyping Service, INSERM-US006 ANEXPLO/CREFRE, Toulouse, France.
Aurore
A
Desquesnes
Phenotyping Service, INSERM-US006 ANEXPLO/CREFRE, Toulouse, France.|Université Toulouse III - Paul Sabatier, Toulouse, France.
Sophie
S
Le Gonidec
INSERM/UPS - US006/CREFRE, Service d'Histopathologie, CHU Purpan, Toulouse, France.
Talal
T
AlSaati
INSERM UMRS 1185, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France.
Isabelle
I
Beau
Inserm, UMR1037 CRCT, F-31000 Toulouse, France.|Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.|CNRS, ERL5294 CRCT, F-31000 Toulouse, France.|Université Toulouse III - Paul Sabatier, Toulouse, France.|Department of Pathology, IUCT, Toulouse, France.|European Research Initiative on ALK-related malignancies (ERIA).
Laurence
L
Lamant
Inserm, UMR1037 CRCT, F-31000 Toulouse, France.|Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.|CNRS, ERL5294 CRCT, F-31000 Toulouse, France.|European Research Initiative on ALK-related malignancies (ERIA).
Fabienne
F
Meggetto
Inserm, UMR1037 CRCT, F-31000 Toulouse, France.|Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.|CNRS, ERL5294 CRCT, F-31000 Toulouse, France.|Université Toulouse III - Paul Sabatier, Toulouse, France.|European Research Initiative on ALK-related malignancies (ERIA).
Estelle
E
Espinos
Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, Paris, France.
Patrice
P
Codogno
Inserm, UMR1037 CRCT, F-31000 Toulouse, France.|Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.|CNRS, ERL5294 CRCT, F-31000 Toulouse, France.|Université Toulouse III - Paul Sabatier, Toulouse, France.|Department of Pathology, IUCT, Toulouse, France.|European Research Initiative on ALK-related malignancies (ERIA).
Pierre
P
Brousset
Inserm, UMR1037 CRCT, F-31000 Toulouse, France.|Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.|CNRS, ERL5294 CRCT, F-31000 Toulouse, France.|European Research Initiative on ALK-related malignancies (ERIA).
Sylvie
S
Giuriato
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D000077547:Crizotinib; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D002738:Chloroquine; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
NPM-ALK; anaplastic large cell lymphoma; autophagy; crizotinib; cytoprotection