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 Gausdal; Anne Simonsen; Jean Paul Thiery; Salem Chouaib; James B Lorens; Agnete Svendsen Tenfjord Engelsen

doi:10.1016/j.jtho.2020.01.015

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

J Thorac Oncol. 2020 Jun;15(6):973-999. doi: 10.1016/j.jtho.2020.01.015. Epub 2020 Feb 1.

Authors

Maria L Lotsberg¹, Katarzyna Wnuk-Lipinska², Stéphane Terry³, Tuan Zea Tan⁴, Ning Lu⁵, Laura Trachsel-Moncho⁶, Gro V Røsland⁷, Muntequa I Siraji⁸, Monica Hellesøy⁹, Austin Rayford⁸, Kirstine Jacobsen¹⁰, Henrik J Ditzel¹¹, Olav K Vintermyr¹², Trever G Bivona¹³, John Minna¹⁴, Rolf A Brekken¹⁵, Bruce Baguley¹⁶, David Micklem⁹, Lars A Akslen¹⁷, Gro Gausdal⁹, Anne Simonsen⁶, Jean Paul Thiery¹⁸, Salem Chouaib¹⁹, James B Lorens⁵, Agnete Svendsen Tenfjord Engelsen²⁰

Affiliations

¹ Centre 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.
² Department of Biomedicine, University of Bergen, Bergen, Norway; BerGenBio ASA, Bergen, Norway.
³ INSERM UMR 1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
⁴ Cancer Science Institute of Singapore, National University of Singapore, Singapore.
⁵ Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway.
⁶ Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷ Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
⁸ Department of Biomedicine, University of Bergen, Bergen, Norway.
⁹ BerGenBio ASA, Bergen, Norway.
¹⁰ Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
¹¹ Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Department of Oncology, Odense University Hospital, Odense, Denmark.
¹² Department of Pathology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
¹³ Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
¹⁴ Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Surgery, Pharmacology and Internal Medicine, UT Southwestern Medical Center, Dallas, Texas.
¹⁵ Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway; Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Departments of Surgery, Pharmacology and Internal Medicine, UT Southwestern Medical Center, Dallas, Texas.
¹⁶ Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
¹⁷ Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
¹⁸ Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway; INSERM UMR 1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Biomedical Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, A-STAR, Singapore; Guangzhou Institutes of Biomedicine and Health, Guangzhou, People's Republic of China; Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong.
¹⁹ Department of Pathology, Haukeland University Hospital, Bergen, Norway; Thumbay Research Institute for Precision Medicine, GMU Ajman, United Arab Emirates.
²⁰ Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway; INSERM UMR 1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France. Electronic address: agnete.engelsen@uib.no.

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.

Keywords: AXL receptor tyrosine kinase; Acquired EGFR TKI resistance; Autophagic flux; NSCLC; Phenotypic plasticity; Tumor immune microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Cell Line, Tumor
Drug Resistance, Neoplasm
ErbB Receptors
Humans
Immunogenic Cell Death
Lung Neoplasms* / drug therapy
Pharmaceutical Preparations*
Protein Kinase Inhibitors / pharmacology

Substances

Pharmaceutical Preparations
Protein Kinase Inhibitors
ErbB Receptors

Abstract

Publication types

MeSH terms

Substances

Grants and funding