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

Oncotarget
Géraldine MitouSylvie Giuriato

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 tha...Continue Reading

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Citations

Dec 1, 2017·Cancers·Julie FrentzelSylvie Giuriato
Jul 8, 2020·Laboratory Medicine·Hassan BoustaniMinoo Shahidi
Apr 4, 2017·Médecine sciences : M/S·Carine JoffreSylvie Giuriato
Mar 24, 2017·Scientific Reports·I-Hsiao ChungKwang-Huei Lin
Feb 2, 2019·Cells·Mojgan Djavaheri-MergnyMagali Humbert
Apr 9, 2016·Oncotarget·Pietro Di FazioThaddeus T Wissniowski
Sep 27, 2018·Oncotarget·André WirriesPietro Di Fazio
Feb 23, 2017·The Journal of International Medical Research·Xiao HanMingqi Ouyang
Nov 4, 2020·The Journal of Clinical Investigation·Annabelle CongrasFabienne Meggetto
Dec 9, 2020·International Journal of Molecular Sciences·Silvia Vega-Rubín-de-CelisSamuel Peña-Llopis
May 28, 2021·Frontiers in Pharmacology·Rafael Fernades CostaJames Oluwagbamigbe Fajemiroye

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Methods Mentioned

BETA
flow cytometry
transfection
PCR
electron microscopy
FACS
xenograft
xenografts
FCS

Software Mentioned

HistoQuant
FlowJo
CompuSyn
Image J
Pannoramic Viewer
GraphPad Prism

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