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

Chapter

Abstract

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.

Keywords

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

Abbreviations

AML

Acute myeloid leukemia

BMDSC

Bone marrow-derived stem cells

CML

Chronic myeloid leukemia

DKK3

Dickkopf-homologue 3

ECM

Extracellular matrix

EGFR

Epidermal growth factor receptor/ErbB-1

EMP

Epithelial-to-mesenchymal plasticity

EMT

Epithelial-to-mesenchymal transition

GISTs

Gastrointestinal stromal tumors

HER2

Human epidermal growth factor receptor 2/ErbB-2

HER3

Human epidermal growth factor receptor 3/ErbB-3

HGF

Hepatocyte growth factor

HIF1α

Hypoxia-inducible factor 1α

HNC

Head and neck cancer

HUVECs

Human umbilical vein endothelial cells

MET

Mesenchymal-to-epithelial transition

MMPs

Matrix metalloproteinases

NSCLC

Non-small cell lung cancer

RTK

Receptor tyrosine kinase

SCC

Squamous cell carcinoma

TK

Tyrosine kinase

TKI

Tyrosine kinase inhibitor

TNBC

Triple-negative breast cancer

VEGF

Vascular endothelial growth factor

VEGFR

Vascular endothelial growth factor receptor

VSMC

Vascular smooth muscle cells

Notes

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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