AXL receptor tyrosine kinase

Gene

The Axl gene is evolutionarily conserved between vertebrate species.

Human AXL is in close vicinity to the BCL3 oncogene, which is at 19q13.1-q13.2. This gene has two different alternatively spliced transcript variants.

Structure

The protein encoded by this gene is a member of the receptor tyrosine kinase subfamily. Although it is similar to other receptor tyrosine kinases, the Axl protein represents a unique structure of the extracellular region that juxtaposes IgL and FNIII repeats.

The AXL protein is characterized by an extracellular structure consisting of two fibronectin type 3-like repeats and two immunoglobulin-like repeats along with its intracellular tyrosine kinase domain.

Function

The AXL receptor transduces signals from the extracellular matrix into the cytoplasm by binding growth factors like vitamin K-dependant protein growth-arrest-specific gene 6 (GAS6). It is involved in the stimulation of cell proliferation, migration, differentiation and survival. Activation of Axl leads to autophosphorylation of its intracellular domain. Proteolytic cleavage of the AXL extracellular domain by the metalloproteinases ADAM10 and ADAM17 can downregulate this signalling activity.

Signalling pathways activated downstream of AXL include PI3K-AKT-mTOR, MEKERK, NF-κB, and JAK/STAT.

This receptor can also mediate cell aggregation by homophilic binding.

AXL protein is expressed in normal tissues, particularly in bone marrow stroma and myeloid cells, and in tumour cells and tumour vasculature. In cancer, AXL is expressed on the tumor cells as well as adjacent immune cells including dendritic cells, macrophages, and NK cells.

Axl is an inhibitor of the innate immune response. The function of activated AXL in normal tissues includes the efficient clearance of apoptotic material and the dampening of TLR-dependent inflammatory responses and natural killer cell activity.

Axl expression on dendritic cells has been shown to limit their maturation and functions by limiting cholesterol mobilization for the assembly of lipid nanodomains at the cell surface.

AXL is a putative driver of diverse cellular processes that are critical for the development, growth, and spread of tumours, including proliferation, invasiveness and migration, epithelial-to-mesenchymal transition, stemness, angiogenesis, and immune modulation. AXL has been implicated as a cancer driver and correlated with poor survival in numerous aggressive tumors including triple-negative breast cancer (TNBC), acute myeloid leukemia (AML), non-small-cell lung cancer (NSCLC), pancreatic cancer and ovarian cancer, among others.

Clinical significance

Axl was first isolated in 1988 and identified as an oncogene in a screen for transforming genes in patients with a chronic myelogenous leukemia- that progressed to 'blast crisis'. Since then, increased AXL expression has been associated with numerous cancers including lung cancer, breast cancer, pancreatic cancer, ovarian cancer, colon cancer and melanoma among others, and shown to have a strong correlation with poor survival outcomes.

AXL has been shown to be a key driver of drug-resistance to targeted therapies, immuno therapies and chemotherapy in various animal models. Based on current knowledge of AXL's role in therapy resistance, future studies will help to determine whether AXL has a translational application as a biomarker for predicting therapeutic response to established drugs.

Recently, AXL has been implicated in chronic fibrotic diseases in several organs, including the liver.

AXL also play an important role in Zika virus and SARS-CoV-2 infection, allowing for entry of the virus into host cells. This phenomenon is known to rely on phosphatidylserine incorporated in the viral envelope during egress, which then binds to AXL via the adapter GAS6. AXL mediates internalization into the endosome from which these viruses escape and initiate replication.

As a drug target

Studies have shown that AXL knockdown leads to downregulation of transcription factors required for EMT, including Slug, Twist, and Zeb1, and to increased expression of E-cadherin.

Cancer

Several drugs classified as "AXL inhibitors" have entered clinical trials; however, many target multiple kinase receptors in addition to AXL. The most advanced AXL selective inhibitor is bemcentinib (BGB324 or R428), an oral small molecule currently in multiple Phase II clinical trials for NSCLC, TNBC, AML and melanoma. Bemcentinib is being pursued as monotherapy and as combination therapy with existing and emerging targeted therapies, immunotherapies and chemotherapy.

A monoclonal antibody targeting AXL (YW327.6S2) and an AXL decoy receptor (GL2I.T) are currently in preclinical development. Additionally, an oral AXL inhibitor (TP-0903) is expected to enter Phase 1 clinical trial in November 2016 (in advanced solid tumours: NCT02729298).

Astellas Pharma is currently testing gilteritinib (ASP2215), a dual FLT3-AXL tyrosine kinase inhibitor in acute myeloid leukemia (AML). In 2017, gilteritinib gained FDA orphan drug status for AML.

These approved drugs and ongoing and pending clinical trials highlight the potentially wide-ranging safety and efficacy of AXL inhibition.

Interactions

AXL receptor tyrosine kinase has been shown to interact with TENC1. Also, it interacts with CBL, GRB2, LCK, NCK2, PIK3R1, PIK3R2, PIK3R3, PLCG1, SOCS1, and TNS2.

References

References

1. (October 1991). "axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase". Molecular and Cellular Biology.
2. "Entrez Gene: AXL AXL receptor tyrosine kinase".
3. (November 1991). "A novel putative tyrosine kinase receptor with oncogenic potential". Oncogene.
4. (2017). "Biomarkers of the Tumor Microenvironment". Springer.
5. (March 2024). "Therapeutic targeting of the functionally elusive TAM receptor family". Nature Reviews. Drug Discovery.
6. (April 2016). "Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance". Cancer Discovery.
7. (February 2017). "Giving AXL the axe: targeting AXL in human malignancy". British Journal of Cancer.
8. (September 1994). "Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis". Blood.
9. (December 2005). "Expression of axl in lung adenocarcinoma and correlation with tumor progression". Neoplasia.
10. (December 2007). "TAM receptors are pleiotropic inhibitors of the innate immune response". Cell.
11. (February 2025). "Cholesterol mobilization regulates dendritic cell maturation and the immunogenic response to cancer". Nature Immunology.
12. (April 2006). "Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival". Proceedings of the National Academy of Sciences of the United States of America.
13. (March 1988). "Transforming genes in chronic myelogenous leukemia". Proceedings of the National Academy of Sciences of the United States of America.
14. (September 2015). "Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation". Journal of Hepatology.
15. (May 2016). "Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells". Cell Stem Cell.
16. (November 2021). "Phosphatidylserine receptors enhance SARS-CoV-2 infection". PLOS Pathogens.
17. (March 2014). "AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells". Oncogene.
18. (July 20, 2017). "Gilteritinib Granted Orphan Drug Status for Acute Myeloid Leukemia". Haymarket Media Inc.
19. (December 2002). "Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin". Biochemical and Biophysical Research Communications.
20. (December 2002). "Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin". Biochemical and Biophysical Research Communications.