AXL receptor tyrosine kinase

Tyrosine-protein kinase receptor UFO is an enzyme that in humans is encoded by the AXL gene.^[5][6] The gene was initially designated as UFO, in allusion to the unidentified function of this protein.^[7] However, in the years since its discovery, research into AXL's expression profile and mechanism has made it an increasingly attractive target, especially for cancer therapeutics. In recent years, AXL has emerged as a key facilitator of immune escape and drug-resistance by cancer cells, leading to aggressive and metastatic cancers.^[8]

AXL is a cell surface receptor tyrosine kinase, part of the TAM family of kinases including TYRO3 and MERTK.^{[citation needed]}

Gene and protein structure

The Axl gene is evolutionarily conserved between vertebrate species. This gene has two different alternatively spliced transcript variants.^[6]

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.^[6]

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.

AXL is in close vicinity to the BCL3 oncogene, which is at 19q13.1-q13.2.^[6]

Function

The AXL receptor transduces signals from the

Signalling pathways activated downstream of AXL include PI3K-AKT-mTOR, MEKERK, NF-κB, and JAK/STAT.[10]

This receptor can also mediate cell aggregation by homophilic binding.^[6]

AXL protein is expressed in normal tissues, particularly in bone marrow stroma and myeloid cells, and in tumour cells and tumour vasculature.^[11][12] 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

Recently, AXL has been implicated in chronic fibrotic diseases in several organs, including the liver.[16]

AXL also play an important role in Zika virus and SARS-CoV-2 infection, allowing for entry of the virus into host cells.^{[17] [18]} 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

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).

These approved drugs and ongoing and pending clinical trials highlight the potentially wide-ranging safety and efficacy of AXL inhibition.[10]

Interactions

AXL receptor tyrosine kinase has been shown to