Oncotarget

Research Papers:

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

Géraldine Mitou _, Julie Frentzel, Aurore Desquesnes, Sophie Le Gonidec, Talal AlSaati, Isabelle Beau, Laurence Lamant, Fabienne Meggetto, Estelle Espinos, Patrice Codogno, Pierre Brousset and Sylvie Giuriato

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Oncotarget. 2015; 6:30149-30164. https://doi.org/10.18632/oncotarget.4999

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Abstract

Géraldine Mitou1,2,3,*, Julie Frentzel1,2,3,*, Aurore Desquesnes4, Sophie Le Gonidec4,7, Talal AlSaati5, Isabelle Beau6, Laurence Lamant1,2,3,7,8,10, Fabienne Meggetto1,2,3,10, Estelle Espinos1,2,3,7,10, Patrice Codogno9, Pierre Brousset1,2,3,7,8,10, Sylvie Giuriato1,2,3,10

1Inserm, UMR1037 CRCT, F-31000 Toulouse, France

2Université Toulouse III-Paul Sabatier, UMR1037 CRCT, F-31000 Toulouse, France

3CNRS, ERL5294 CRCT, F-31000 Toulouse, France

4Phenotyping Service, INSERM-US006 ANEXPLO/CREFRE, Toulouse, France

5INSERM/UPS - US006/CREFRE, Service d’Histopathologie, CHU Purpan, Toulouse, France

6INSERM UMRS 1185; Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France

7Université Toulouse III - Paul Sabatier, Toulouse, France

8Department of Pathology, IUCT, Toulouse, France

9Institut Necker Enfants-Malades, INSERM U1151-CNRS UMR 8253, Paris, France

10European Research Initiative on ALK-related malignancies (ERIA)

*These authors have contributed equally to this work

Correspondence to:

Sylvie Giuriato, e-mail: sylvie.giuriato@inserm.fr

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

Received: March 02, 2015     Accepted: August 07, 2015     Published: August 17, 2015

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.


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