AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells.
AXL receptor tyrosine kinase
Acquired EGFR TKI resistance
Autophagic flux
NSCLC
Phenotypic plasticity
Tumor immune microenvironment
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
19
08
2019
revised:
29
12
2019
accepted:
19
01
2020
pubmed:
6
2
2020
medline:
7
1
2021
entrez:
5
2
2020
Statut:
ppublish
Résumé
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. 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. 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). 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.
Identifiants
pubmed: 32018052
pii: S1556-0864(20)30055-1
doi: 10.1016/j.jtho.2020.01.015
pmc: PMC7397559
mid: NIHMS1609069
pii:
doi:
Substances chimiques
Pharmaceutical Preparations
0
Protein Kinase Inhibitors
0
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
973-999Subventions
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224081
Pays : United States
Informations de copyright
Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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