Targeting Axl-GAS6—a new option for tumor therapy

Tumor drug resistance is a major problem limiting the clinical efficacy of therapeutic drugs. Recently, an article published by a Spanish research team revealed that cells resistant to Her2 showed high expression of Axl. Inhibition of the Her2-Axl heterodimer can reverse the drug resistance of Her2, and knockout of the Axl gene enhances the sensitivity of cells to trastuzumab, confirming the role of Axl in tumor drug resistance [1]. It also provides a reference for the combined treatment regimen of Her2.

Figure 1. Protein structures of Axl and GAS6 [2]. 

Axl belongs to the large family of receptor tyrosine kinase’s. The extracellular region consists of two Ig domains and two FNIII domains, and the intracellular tyrosine kinase domain has a cleavage site outside its transmembrane region, which can be cleaved into soluble extracellular fragments by proteases. GAS6 is the only ligand of Axl found so far, and it is highly expressed together with Axl in various malignant tumors, such as breast cancer, lung cancer, esophageal cancer and so on. After GAS6 binds to Axl to form a complex, it will further form a dimerized homologous complex, which activates PI3K/AKT, MAPK/ERK and other pathways through the intracellular segment of Axl to regulate cell proliferation and metastasis, resulting in an immunosuppressive tumor microenvironment. It is also related to the poor prognosis of many cancer types. In addition, Axl can form heterodimers with other proteins such as Tyro3, Mer, and Her2, and can also form homodimers by itself. These bindings are independent of GAS6 and are mainly involved in intercellular adhesion and angiogenesis.

Figure 2. Axl-GAS6 signaling pathway [3].

There are two main strategies to develop drugs targeting Axl-GAS6. One is to directly inhibit Axl, and the other is to inhibit GAS6 to prevent its binding to Axl, i.e., ligand capture. These drugs are suitable for tumor drug resistance therapy or universal tumor therapy. The types of drugs targeting Axl include small molecule inhibitors, antibody drugs, ADCs and CAR-Ts. Small molecule inhibitors targeting the intracellular segment of Axl to inhibit tyrosine kinase activity, such as AB-329, BGB324, and TP-0903, are already in clinical practice. In addition, XZB-0004 introduced by Xuanzhu Bio and Penpulimab PD-1 monoclonal antibody of Chia Tai Tianqing have been used in clinical combination therapy for solid tumors, suggesting that combination therapy will be one direction. Macromolecular drugs are mainly focused on ADCs, but two ADC drugs targeting Axl developed by Genmab and ADC Therapeutics were unfortunately terminated due to failing to meet clinical expectations (see Table 1). Industry analysis may be the off-target effects of drugs and ADCs. Toxicity results, which also shows the need for more in-depth research on target-related mechanisms and drug design. In terms of GAS6, Batiraxcept (SD-229), a fusion protein drug that can neutralize GAS6 with high specificity, has been introduced by Aravive. It has been combined with Envafolimab or Lenvatinib to develop treatments for non-small cell lung cancer, clear renal cell carcinoma and urothelial carcinoma. The Phase Ib/II clinical study in patients with advanced solid tumors has recently been reviewed by CDE.

Table 1. Some targeted drugs for Axl and GAS6

The drugs of Axl are still small molecule inhibitors, which may benefit from the advantages of small molecules in oral utilization. On the other hand, targeting GAS6 may also impair the efficacy due to the Axl-independent GAS6-dependent bypass pathway. Like the setbacks of ADC drugs, these challenges have stimulated the development of macromolecular drugs to some extent. Moreover, drugs targeting Axl-GAS6 show better effects when combined with other tumor treatment options, so the prospects are still promising, and as more detailed mechanisms are discovered, the Axl-GAS6 drug market will surely receive more attention.

For the Axl-GAS6 pathway, KACTUS has specially developed highly active Axl and GAS6 proteins expressed in mammalian cell systems, to ensure they have the correct conformation and protein function. The products come in various forms such as functional domain, tags and species, and will aid in the development of Axl and GAS6 drugs. 

Product Data

Recombinant Human Axl protein (AXL-HM201, C-hFc) developed by KACTUS can specifically bind to ligand GAS6 (GAS-HM116, C-His) with an EC50 value of 7.5ng/mL.

Recombinant Human GAS6 protein (GAS-HM116, C-His) developed by KACTUS can specifically bind to GAS6 antibody with an EC50 value of 11.7ng/mL. 

KACTUS Products