Its exceptional role in GBM was presented in previous studies showing that experimental inhibition of the RTK-AXL pathway with dominant negative-mutant glioma cells of AXL receptor (SF126 AXL-DN) suppresses glioma growth and prolongs survival in orthotopic tumor model in mice 1).
Dysregulation of Axl and its ligand growth arrest-specific 6 (GAS6) is implicated in the pathogenesis of several human cancers.
In a study, Li et al. used RNAi and monoclonal antibodies to assess further the oncogenic potential of Axl. They show that Axl knockdown reduces growth of lung and breast cancer xenograft tumors. Inhibition of Axl expression attenuates breast cancer cell migration and inhibits metastasis to the lung in an orthotopic model, providing the first in vivo evidence that links Axl directly to cancer metastasis. Axl knockdown in endothelial cells impaired tube formation and this effect was additive with anti-vascular endothelial growth factor (VEGF). Further analysis demonstrated that Axl regulates endothelial cell functions by modulation of signaling through angiopoietin/Tie2 and Dickkopf (DKK3) pathways. They have developed and characterized Axl monoclonal antibodies that attenuate non-small cell lung carcinoma xenograft growth by downregulation of receptor expression, reducing tumor cell proliferation and inducing apoptosis.
This data demonstrate that Axl plays multiple roles in tumorigenesis and that therapeutic antibodies against Axl may block Axl functions not only in malignant tumor cells but also in the tumor stroma. The additive effect of Axl inhibition with anti-VEGF suggests that blocking Axl function could be an effective approach for enhancing antiangiogenic therapy 2).
In human gliomas, Axl and Gas6 are frequently overexpressed in both glioma and vascular cells and predict poor prognosis in GBM patients. Results indicate that specific targeting of the Axl/Gas6 signaling pathway may represent a potential new approach for glioma treatment 3).
The gene was initially designated as UFO, in allusion to the unidentified function of this protein.
The AXL protein is a cell surface receptor.
The Axl gene is evolutionarily conserved between vertebrate species. This gene has two different alternatively spliced transcript variants.
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 receptor transduces signals from the extracellular matrix into the cytoplasm by binding growth factors like vitamin K-dependent protein growth-arrest-specific gene 6 (GAS6). It is involved in the stimulation of cell proliferation.
This receptor can also mediate cell aggregation by homophilic binding.
Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival.
Axl is a chronic myelogenous leukemia-associated oncogene and also associated with colon cancer and melanoma. It is in close vicinity to the BCL3 oncogene, which is at 19q13.1-q13.2.
AXL may play an important role in Zika virus infection, allowing for entry of the virus into host cells.
There is ongoing research to develop possible drugs to target this signalling pathway and treat cancers.
In 2014 those in clinical trials included:Table 2 LY2801653, MP-470 (Amuvatinib), SKI-606 (Bosutinib), MGCD 265, ASP2215, XL184 (Cabozantinib), GSK1363089/XL880 (Foretinib), SGI-7079, and R428 (BGB324).
e.g. Astellas Pharma is currently testing ASP2215 (Gilteritinib), a dual FLT3-AXL tyrosine kinase inhibitor in acute myeloid leukemia (AML).
BGB324 (a selective AXL inhibitor) is in clinical trials for AML and non-small cell lung cancer (NSCLC).
AXL receptor tyrosine kinase has been shown to interact with TENC1.
Xu et al. discover that receptor tyrosine kinase AXL is a transcriptional target of BCL6 in GBM and mediates partially the regulatory effects of BCL6 on both MEK-ERK (mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase) and S6K-RPS6 (ribosomal protein S6 kinase-ribosomal protein S6) axes. Similar to BCL6 silencing, depletion of AXL profoundly attenuates GBM proliferation both in vitro and in vivo. Moreover, targeted inhibition of BCL6/nuclear receptor corepressor 1 (NCoR) complex by peptidomimetic inhibitor not only significantly decreases AXL expression and the activity of MEK-ERK and S6K-RPS6 cascades but also displays a potent antiproliferative effect against GBM cells. Together, these findings uncover a glioma-promoting role of BCL6 and provide the rationale of targeting BCL6 as a potential therapeutic approach 4).
EGFR inhibition triggers a rapid adaptive response driven by increased tumor necrosis factor (TNF) secretion, which leads to activation in turn of c-Jun N-terminal kinase (JNK), the Axl receptor tyrosine kinase and extracellular signal-regulated kinases (ERK). Inhibition of this adaptive axis at multiple nodes rendered glioma cells with primary resistance sensitive to EGFR inhibition. The findings provide a possible explanation for the failures of anti-EGFR therapy in GBM and suggest a new approach to the treatment of EGFR-expressing GBM using a combination of EGFR and TNF inhibition 5)
Data strongly suggest that targeting RTK-AXL with BMS-777607 could represent a novel and potent regimen for the treatment of primary and recurrent GBM 6).
Receptor tyrosine kinase AXL (RTK-AXL) is regarded as a suitable target in glioblastoma (GBM) therapy. Since AXL kinase inhibitors are about to get approval for clinical use, patients with a potential benefit from therapy targeting AXL need to be identified.
Onken et al. therefore assessed the expression pattern of Phospho-AXL (P-AXL), the biologically active form of AXL, in 90 patients with newly diagnosed GBM, which was found to be detectable in 67 patients (corresponding to 74%). They identified three main P-AXL expression patterns: i) exclusively in the tumor vasculature (13%), ii) in areas of hypercellularity (35%), or iii) both, in the tumor vasculature and in hypercellular areas of the tumor tissue (52%). Pattern iii) is associated with significant decrease in overall survival (Hazard ratio 2.349, 95% confidence interval 1.069 to 5.162, *p=0.03).
This data suggest that P-AXL may serve as a therapeutic target in the majority of GBM patients 7).
Yen et al. demonstrated that n-Butylidenephthalide (BP) reduced the expression of AXL and stemness related genes in a dose-dependent manner. The migratory and invasive capabilities of GBM stem-like cells could be reduced by AXL/EZH2. Finally, in the overexpression of AXL, EZH2 and Sox2 by transfection in GBM stem-like cells, we found that AXL/EZH2/TGF-ꞵ1, but not Sox2, might be a key regulator in tumor invasion, migration and EMT. These results might help in the development of a new anticancer compound and can be a target for treating GBM 8).