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

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

Mitou G1,2,3, Frentzel J1,2,3, Desquesnes A4, Le Gonidec S4,5, AlSaati T6, Beau I7, Lamant L1,2,3,5,8,9, Meggetto F1,2,3,9, Espinos E1,2,3,5,9, Codogno P10, Brousset P1,2,3,5,8,9, Giuriato S1,2,3,9.

Author information

1
Inserm, UMR1037 CRCT, F-31000 Toulouse, France.
2
Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France.
3
CNRS, ERL5294 CRCT, F-31000 Toulouse, France.
4
Phenotyping Service, INSERM-US006 ANEXPLO/CREFRE, Toulouse, France.
5
Université Toulouse III - Paul Sabatier, Toulouse, France.
6
INSERM/UPS - US006/CREFRE, Service d'Histopathologie, CHU Purpan, Toulouse, France.
7
INSERM UMRS 1185, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France.
8
Department of Pathology, IUCT, Toulouse, France.
9
European Research Initiative on ALK-related malignancies (ERIA).
10
Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, Paris, France.

Abstract

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

PMID:
26338968
PMCID:
PMC4745787
DOI:
10.18632/oncotarget.4999
[Indexed for MEDLINE]
Free PMC Article

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