Back to Search Start Over

AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells.

Authors :
Lotsberg ML
Wnuk-Lipinska K
Terry S
Tan TZ
Lu N
Trachsel-Moncho L
Røsland GV
Siraji MI
Hellesøy M
Rayford A
Jacobsen K
Ditzel HJ
Vintermyr OK
Bivona TG
Minna J
Brekken RA
Baguley B
Micklem D
Akslen LA
Gausdal G
Simonsen A
Thiery JP
Chouaib S
Lorens JB
Engelsen AST
Source :
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer [J Thorac Oncol] 2020 Jun; Vol. 15 (6), pp. 973-999. Date of Electronic Publication: 2020 Feb 01.
Publication Year :
2020

Abstract

Introduction: Acquired cancer therapy resistance evolves under selection pressure of immune surveillance and favors mechanisms that promote drug resistance through cell survival and immune evasion. AXL receptor tyrosine kinase is a mediator of cancer cell phenotypic plasticity and suppression of tumor immunity, and AXL expression is associated with drug resistance and diminished long-term survival in a wide range of malignancies, including NSCLC.<br />Methods: We aimed to investigate the mechanisms underlying AXL-mediated acquired resistance to first- and third-generation small molecule EGFR tyrosine kinase inhibitors (EGFRi) in NSCLC.<br />Results: We found that EGFRi resistance was mediated by up-regulation of AXL, and targeting AXL reduced reactivation of the MAPK pathway and blocked onset of acquired resistance to long-term EGFRi treatment in vivo. AXL-expressing EGFRi-resistant cells revealed phenotypic and cell signaling heterogeneity incompatible with a simple bypass signaling mechanism, and were characterized by an increased autophagic flux. AXL kinase inhibition by the small molecule inhibitor bemcentinib or siRNA mediated AXL gene silencing was reported to inhibit the autophagic flux in vitro, bemcentinib treatment blocked clonogenicity and induced immunogenic cell death in drug-resistant NSCLC in vitro, and abrogated the transcription of autophagy-associated genes in vivo. Furthermore, we found a positive correlation between AXL expression and autophagy-associated gene signatures in a large cohort of human NSCLC (n = 1018).<br />Conclusion: Our results indicate that AXL signaling supports a drug-resistant persister cell phenotype through a novel autophagy-dependent mechanism and reveals a unique immunogenic effect of AXL inhibition on drug-resistant NSCLC cells.<br /> (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1556-1380
Volume :
15
Issue :
6
Database :
MEDLINE
Journal :
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Publication Type :
Academic Journal
Accession number :
32018052
Full Text :
https://doi.org/10.1016/j.jtho.2020.01.015