AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications

Abstract

Molecular targeted therapy for cancer has been a research hotspot for decades. AXL is a member of the TAM family with the high-affinity ligand growth arrest-specific protein 6 (GAS6). The Gas6/AXL signalling pathway is associated with tumour cell growth, metastasis, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, drug resistance, immune regulation and stem cell maintenance. Different therapeutic agents targeting AXL have been developed, typically including small molecule inhibitors, monoclonal antibodies (mAbs), nucleotide aptamers, soluble receptors, and several natural compounds. In this review, we first provide a comprehensive discussion of the structure, function, regulation, and signalling pathways of AXL. Then, we highlight recent strategies for targeting AXL in the treatment of cancer.AXL-targeted drugs, either as single agents or in combination with conventional chemotherapy or other small molecule inhibitors, are likely to improve the survival of many patients. However, future investigations into AXL molecular signalling networks and robust predictive biomarkers are warranted to select patients who could receive clinical benefit and to avoid potential toxicities.

Keywords: AXL; Cancer; Inhibitor; Receptor tyrosine kinase; Signaling pathway.

Fig. 1

Basic structure, signaling pathways and activation of AXL. (a) Schematic diagram representing the structure of AXL receptor tyrosine kinase. AXL is composed of two immunoglobulin (Ig)-like repeats and two fibronectin type III (Fro III)-like repeats, a transmembrane domain and an intracellular kinase domain. (b) AXL signaling networks upon classical GAS6-mediated activation function in proliferation and survival, migration and invasion, epithelial-to-mesenchymal transition (EMT), angiogenesis, resistance to therapy, immune suppression, and stem cell maintenance. (c) AXL activation patterns: 1) classical GAS6 ligand-dependent dimerization; 2) Gas6 ligand-independent dimerization; 3) heterophilic dimerazation of AXL with a TAM family member like MER or TYRO3; 4) heterophilic dimerazation of AXL with a non-TAM family protein; and 5) ligand-independent activation of AXL through transcellular homophilic binding

Fig. 2

Different therapeutic agents targeting AXL have been developed, including 1) small molecule inhibitors that block AXL auto-phosphorylation and kinase activities; 2) anti-AXL monoclonal antibodies (mAbs); 3) nucleotide aptamers; 4) soluble receptors; and 5) several natural compounds