|CDCB157214||Mouse AXL ORF clone (NM_009465.3)||Inquiry|
|CDCB182589||Rabbit AXL ORF clone (XM_008249707.1)||Inquiry|
|CDCR032594||Human AXL ORF clone (NM_021913.3)||Inquiry|
|CDCR032600||Mouse Axl ORF clone (NM_001190975.1)||Inquiry|
|CDCR032602||Mouse Axl ORF clone (NM_001190974.1)||Inquiry|
|CDCR281311||Human AXL ORF Clone(NM_001699.4)||Inquiry|
|CDCR369869||Rat Axl ORF Clone(NM_001013147.1)||Inquiry|
|CDCR379938||Rat Axl ORF Clone(NM_031794.1)||Inquiry|
|CDCS410387||Human AXL ORF Clone (BC032229)||Inquiry|
|CDFG021624||Mouse Axl cDNA Clone(NM_001190975.1)||Inquiry|
|CDFR002871||Rat Axl cDNA Clone(NM_001013147.1)||Inquiry|
|CDFR012924||Rat Axl cDNA Clone(NM_031794.1)||Inquiry|
|MiUTR1H-00753||AXL miRNA 3'UTR clone||Inquiry|
|MiUTR1H-00754||AXL miRNA 3'UTR clone||Inquiry|
|MiUTR1R-00488||AXL miRNA 3'UTR clone||Inquiry|
|MiUTR1R-00489||AXL miRNA 3'UTR clone||Inquiry|
|SHG087411||shRNA set against Human AXL(NM_001699.4)||Inquiry|
|SHG087517||shRNA set against Rat Axl(NM_031794.1)||Inquiry|
|SHG087521||shRNA set against Human AXL(NM_021913.3)||Inquiry|
|SHG087527||shRNA set against Rat Axl(NM_001013147.1)||Inquiry|
|SHG087545||shRNA set against Rat Axl(NM_031794.1)||Inquiry|
|SHH243962||shRNA set against Human AXL (NM_001699.4)||Inquiry|
|SHH243966||shRNA set against Mouse AXL (NM_009465.4)||Inquiry|
|SHH243970||shRNA set against Rat AXL (NM_001013147.1)||Inquiry|
AXL (AXL receptor tyrosine kinase) was originally discovered from chronic myeloid leukemia cells. The AXL gene is located at 19q13.2 and consists of 20 exons. Structurally, AXL consists of three parts: the extracellular domain (two immunoglobulin regions (Ig) and two fibronectin III (FNIII)-like regions, the intracellular domain (tyrosine kinase activation region), and the transmembrane region. The ligand for AXL is the vitamin K-dependent ligand - growth arrest - specific protein 6(Gas6), and AXL activation is dependent on the presence of Gas6 ligand and Phosphatidylserine (PS). Under physiological conditions, when the affinity of Gas6 for AXL is high enough, both can be combined, but Gas6 can fully activate AXL only in the presence of PS.
Transcription factors such as specific protein 1 and specific protein 3 bind to the promoter of the AXL gene and regulate AXL expression. AXL is expressed in endothelial cells and is involved in angiogenesis. Preclinical studies have shown that inhibition of AXL in vitro enhances the anti-angiogenic effect of anti-vascular endothelial growth factor and reduces the formation of vascular endothelial cells. In immune cells, activation of AXL inhibits the release of pro-inflammatory cytokines, so activation of AXL-mediated signaling may help create an immune-tolerant environment that promotes tumor growth. In preclinical studies by Paolino et al., targeted targeting of AXL or its downstream signaling pathways in natural killer cells promotes an anti-cancer immune response in a mouse model of melanoma and breast cancer, suggesting that inhibition of AXL can be applied to tumor immunity treatment.
Figure 1. AXL overexpression and activation of downstream signaling pathways. (Scaltriti, et al. 2016).
The Role of AXL in Tumors
AXL and epithelial-mesenchymal transition (EMT) are epithelial cells that have migrated and infiltrated under some factors, and become cells with mesenchymal cell morphology and characteristics, which are important phenomena in tumor development and progression. The expression and activation of AXL are closely related to the interstitial phenotype of tumor cells. AXL promotes the invasion ability of tumor cells by promoting EMT, increases the probability of metastasis and produces drug resistance, resulting in poor therapeutic effect and affecting the prognosis of patients. Scaltriti et al. analyzed the epithelial stroma phenotypes in non-small cell lung cancer (NSCLC) tissue samples and 54 NSCLC cell lines. The result showed that AXL is highly correlated with EMT in protein and mRNA expression levels.
Inhibition of tumor cell apoptosis leads to the infinite growth of tumor cells, and apoptosis disorder is closely related to tumor development. AXL is related to the apoptosis of tumor cells. It has been confirmed by Western blotting on gastric cancer tissues and adjacent normal tissues that AXL can up-regulate the expression of anti-apoptotic proteins and decrease the activation of apoptotic proteins. It can prevent tumor cells from initiating a death program that inhibits tumor cell apoptosis. Tumor cell dormancy is the result of relative balance between tumor cell apoptosis and proliferation. It is the main reason for malignant tumors to be difficult to cure. Cackowski et al. found that the expression of AXL was related to the dormancy state of prostate cancer cells. Gas6 in osteoblasts activates AXL in prostate cancer cells, and this process plays an important role in establishing dormancy in prostate cancer cells.
When AXL is overexpressed, AXL will obviously exhibits mitogen activity, causing tumor cells to proliferate. This overexpression is associated with poor clinical treatment. Studies have shown that in tumor cells, AXL expression of mRNA and protein levels increased, and it was related to some special transcription factors. For example, mutant p53, Yes - associated protein 1 in NSCLC, Hypoxia-inducible factor- 1 in renal cell carcinoma. AXL can also be expressed by a variety of epigenetic regulation, and hypermethylation of the AXL promoter region results in down-regulation of AXL expression. In addition, high expression of AXL is also associated with heat shock protein 90 (HSP90), and AXL expression is down-regulated when HSP90 is inhibited.
AXL is overexpressed in high-invasive breast cancer cell lines but not in mildly invasive breast cancer cell lines, suggesting that AXL expression is associated with invasiveness and metastasis in breast cancer cell lines. Estrogen receptors can cause overexpression of AXL and increase mammary epithelial cell proliferation, mutation, and apoptosis. Wang et al. confirmed that high expression of tazarotene-inducible gene 1 (TIG1) in inflammatory breast cancer promotes tumor growth and invasion, and TIG1 binds itself to AXL protein by inhibiting its lysosomal degradation in vivo. This indicates AXL may be an important target for the treatment of inflammatory breast cancer.
AXL and Drugs
Overexpression of AXL promotes the progression of various cancers, including the development, progression, invasion, and metastasis of malignant tumors. A number of drug companies are currently developing anti-AXL inhibitors and multi-target kinase inhibitors that also inhibit AXL. AXL inhibitors will become an important new anti-cancer drug. A variety of non-specific multi-kinase inhibitors have been developed worldwide that target AXL receptors in a variety of tyrosine kinases. The most representative of these is the small molecule inhibitor Cabozinidinib, which has both anti-RET activity and anti-vascular endothelial growth factor receptor, MET, Flt3, Kit, and AXL roles, and is currently approved for the treatment of medullary thyroid cancer.
There are also a number of multi-target kinase inhibitors targeting AXL that are in clinical trials. Wu's research indicates that the type II ATP competitive multi-target kinase inhibitor ly2801653 targets MET, AXL and MST1R. In a multi-xenograft tumor mouse model, ly2801653 inhibits tumor cell proliferation and migration, reducing tumor activity, suitable for patients with advanced cancer. The novel ATP-competitive tyrosine kinase inhibitor s49076 targets MET, AXL/MER and FGFR1 /2 /3, and inhibits autophosphorylation of receptor tyrosine kinase and its downstream signals both in vivo and in vitro. Sheridan found that another novel small molecule inhibitor, R428 (BGB324), which is currently undergoing Phase II clinical trials, acts on the carboxy-terminal Tyr821 site, effectively inhibiting AXL phosphorylation and subsequently activating the AKT pathway.
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