The Role of Axl Receptor Tyrosine Kinase in Tumor Cell Plasticity and Therapy Resistance



In spite of the advances in cancer treatment over several decades, resistance to antitumor therapy continues to confound current treatment strategies. Recent insights into the epigenetic heterogeneity of cancer have emphasized a need to address the underlying mechanisms driving tumor cell plasticity. Epithelial-to-mesenchymal transition (EMT)-related transdifferentiation programs are prevalent in aggressive tumors displaying a drug-resistant, invasive, and immune-evasive phenotype. Novel therapeutically actionable targets are needed in order to disable tumor plasticity mechanisms. The Axl receptor tyrosine kinase has a remarkably broad association with aggressive and therapy-resistant cancers, and the understanding that Axl is not a traditional oncogenic driver as first envisioned, but rather involved in regulating tumor cell plasticity related to the EMT program has provided a framework to understand the role of Axl-mediated signal transduction in cancer. Accordingly, a growing number of studies have demonstrated that Axl signaling is required to maintain tumor plasticity and resistance to cytotoxic and targeted anticancer agents. Novel Axl-targeting agents are emerging, facilitating clinical translation of novel combination approaches dedicated to reverse the plasticity-mediated resistance mechanisms and potentiate current anticancer treatments. In this chapter, we describe the unique roles of the Axl receptor tyrosine kinase in tumor cell plasticity and therapeutic resistance and provide an update on Axl-targeting agents entering clinical trials.


Axl EMT EMP Plasticity Drug resistance Targeted therapy Clinical trials Biomarker Tumor microenvironment Tyrosine kinase inhibitors 



Acute myeloid leukemia


Bone marrow-derived stem cells


Chronic myeloid leukemia


Dickkopf-homologue 3


Extracellular matrix


Epidermal growth factor receptor/ErbB-1


Epithelial-to-mesenchymal plasticity


Epithelial-to-mesenchymal transition


Gastrointestinal stromal tumors


Human epidermal growth factor receptor 2/ErbB-2


Human epidermal growth factor receptor 3/ErbB-3


Hepatocyte growth factor


Hypoxia-inducible factor 1α


Head and neck cancer


Human umbilical vein endothelial cells


Mesenchymal-to-epithelial transition


Matrix metalloproteinases


Non-small cell lung cancer


Receptor tyrosine kinase


Squamous cell carcinoma


Tyrosine kinase


Tyrosine kinase inhibitor


Triple-negative breast cancer


Vascular endothelial growth factor


Vascular endothelial growth factor receptor


Vascular smooth muscle cells


Conflict of Interest Statement

J.B.L. has ownership interest in BerGenBio AS. The remaining authors do not declare any potential conflicts of interest.


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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Kjersti T. Davidsen
    • 1
  • Gry S. Haaland
    • 1
  • Maria K. Lie
    • 1
  • James B. Lorens
    • 1
  • Agnete S. T. Engelsen
    • 1
  1. 1.Department of Biomedicine, Centre for Cancer BiomarkersUniversity of BergenBergenNorway

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