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

Maria L Lotsberg1, Katarzyna Wnuk-Lipinska2, Stéphane Terry3

  • 1Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway.

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
|February 5, 2020
PubMed
Abstract

Insights

AXL receptor tyrosine kinase (AXL) drives acquired resistance to EGFR inhibitors in non-small cell lung cancer (NSCLC) via an autophagy-dependent mechanism. Targeting AXL with bemcentinib inhibits this resistance and induces immunogenic cell death in NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Acquired resistance to cancer therapies, like EGFR inhibitors (EGFRi), is a major clinical challenge in NSCLC.
  • AXL receptor tyrosine kinase (AXL) is implicated in cancer cell survival, immune evasion, and drug resistance.
  • AXL expression correlates with poor prognosis in various cancers, including NSCLC.

Purpose of the Study:

  • To elucidate the mechanisms of AXL-mediated acquired resistance to EGFR inhibitors in NSCLC.
  • To investigate the therapeutic potential of targeting AXL in overcoming EGFR inhibitor resistance.

Main Methods:

  • Investigated AXL-mediated resistance to first- and third-generation EGFR inhibitors in NSCLC models.
  • Utilized small molecule inhibitor bemcentinib and siRNA for AXL targeting.
  • Assessed MAPK pathway reactivation, autophagic flux, clonogenicity, and immunogenic cell death.
  • Correlated AXL expression with autophagy gene signatures in a human NSCLC cohort (n=1018).

Main Results:

  • EGFR inhibitor resistance was mediated by AXL upregulation.
  • Targeting AXL reduced MAPK pathway reactivation and blocked acquired resistance in vivo.
  • AXL-expressing resistant cells showed increased autophagic flux.
  • Bemcentinib inhibited autophagic flux, blocked clonogenicity, induced immunogenic cell death, and abrogated autophagy gene transcription.
  • A positive correlation was found between AXL expression and autophagy gene signatures in NSCLC patients.

Conclusions:

  • AXL signaling promotes a drug-resistant persister cell phenotype through a novel autophagy-dependent mechanism.
  • AXL inhibition demonstrates a unique immunogenic effect on drug-resistant NSCLC cells.
  • Targeting AXL represents a promising strategy to overcome acquired resistance to EGFR inhibitors in NSCLC.
Keywords:
AXL receptor tyrosine kinaseAcquired EGFR TKI resistanceAutophagic fluxNSCLCPhenotypic plasticityTumor immune microenvironment

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