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

Maria L. Lotsberg, Katarzyna Wnuk-Lipinska, Stéphane Terry, Tuan Zea Tan, Ning Lu, Laura Trachsel-Moncho, Gro V. Røsland, Muntequa I. Siraji, Monica Hellesøy, Austin Rayford, Kirstine Jacobsen, Henrik J. Ditzel, Olav K. Vintermyr, Trever G. Bivona, John Minna, Rolf A. Brekken, Bruce Baguley, David Micklem, Lars A. Akslen, Gro GausdalAnne Simonsen, Jean Paul Thiery, Salem Chouaib, James B. Lorens, Agnete Svendsen Tenfjord Engelsen

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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. 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. 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). 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.

Original languageEnglish (US)
Pages (from-to)973-999
Number of pages27
JournalJournal of Thoracic Oncology
Volume15
Issue number6
DOIs
StatePublished - Jun 2020

Keywords

  • AXL receptor tyrosine kinase
  • Acquired EGFR TKI resistance
  • Autophagic flux
  • NSCLC
  • Phenotypic plasticity
  • Tumor immune microenvironment

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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