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The Role of AXL Receptor Tyrosine Kinase in Cancer Cell Plasticity and Therapy Resistance

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Biomarkers of the Tumor Microenvironment

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Abstract

Therapy resistance continues to confound all available cancer therapies, including immune checkpoint inhibitors. The astonishing heterogeneity and plasticity of cancers limit long-term therapeutic benefit, and recent insights into the epigenetic heterogeneity of cancers have emphasized a need to address the underlying mechanisms driving cancer cell plasticity. Epithelial-to-mesenchymal transition (EMT)-related trans-differentiation 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. AXL receptor tyrosine kinase has a remarkably broad association with aggressive and therapy-resistant cancers and has emerged as a promising therapeutic target. Recent research has revealed that AXL is not a traditional oncogenic driver as first envisioned, but rather AXL is involved in regulating cancer cell plasticity related to the EMT program. This new knowledge 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 cancer cell plasticity and resistance to cytotoxic and targeted anti-cancer agents, as well as immune checkpoint inhibition. Several AXL-targeting agents are currently being explored in clinical trials dedicated to reverse the plasticity-mediated resistance mechanisms and potentiate current anti-cancer treatments. In this chapter, we aim to explore the unique roles of the AXL receptor tyrosine kinase in cancer cell plasticity and therapeutic resistance and discuss the alternative ways of targeting AXL in clinical trials.

AXL is a mediator of Epithelial Mesenchymal Plasticity (EMP) in normal and malignant cells.

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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

EMT:

Epithelial-to-mesenchymal transition

EMP:

Epithelial-to-mesenchymal plasticity

GAS6:

Growth arrest specific 6

GIST:

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

HNSCC:

Head- and neck-squamous cell carcinoma

HUVECs:

Human umbilical vein endothelial cells

MET:

Mesenchymal-to-epithelial transition

MMPs:

Matrix metalloproteinases

NSCLC:

Non-small cell lung cancer

PS:

Phosphatidyl serine

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

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Acknowledgments

Parts of the text, tables, and figure was published in the first edition of “Biomarkers of the Tumor Microenvironment: Basic Studies and Practical applications” (ISBN 978-3-319-39145-8). The contents are reprinted in this updated version of the book chapter with permission from the publisher: Springer Nature.

Conflict of interest statement: J.B.L. is the founder of BerGenBio ASA. The remaining authors declare no potential conflicts of interest.

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  1. Maria L. Lotsberg and Kjersti T. Davidsen contributed equally to this publication.

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  1. Department of Biomedicine, Centre for Cancer Biomarkers CCBIO, Norwegian Center of Excellence, Faculty of Medicine, University of Bergen, Bergen, Norway

    Maria L. Lotsberg, Kjersti T. Davidsen, Stacey D’Mello Peters, Gry S. Haaland, Austin Rayford, James B. Lorens & Agnete S. T. Engelsen

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    Randolph S. Watnick

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Lotsberg, M.L. et al. (2022). The Role of AXL Receptor Tyrosine Kinase in Cancer Cell Plasticity and Therapy Resistance. In: Akslen, L.A., Watnick, R.S. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-030-98950-7_18

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