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.

Regulation of efferocytosis as a novel cancer therapy

“…For example, TAM receptors are a type of indirect PS receptors, and growth arrest-specific 6 (Gas6) and Protein S are bridging molecules that facilitate the binding of PS on apoptotic cells to TAM receptors (Tyro3, Axl and MerTK) on phagocytes [37]. Further, Gas 6 binds to all three receptors, while Protein S only binds to Tyro3 and MerTK [38]. Milk fat globule epidermal growth factor-8 (MFG-E8) bridges between PS and α v β 3 /α v β 5 integrins, another type of indirect PS receptors [39].…”

“…Axl is typically activated by the Gas6 ligand, and the affinity of Gas6 for Axl is higher than to Tyro3 and MerTK receptors [62]. The Gas6/Axl signaling pathway influences cancer development and progression through its effect on tumor cell proliferation, invasion, metastasis, epithelialmesenchymal transition (EMT), and angiogenesis [38,63,64]. A previous study demonstrated that Axl is required for EMT, which promotes metastasis of HER-2 positive breast cancer [65].…”

“…There are currently five types of Axl targeting agents under development. These agents include small-molecule TKIs, nucleotide aptamers, monoclonal antibodies (mAbs), soluble receptors, and several natural compounds [38]. Research on reputable Axl inhibitors, especially the TKIs, has now progressed into clinical trial phases [38].…”

“…These agents include small-molecule TKIs, nucleotide aptamers, monoclonal antibodies (mAbs), soluble receptors, and several natural compounds [38]. Research on reputable Axl inhibitors, especially the TKIs, has now progressed into clinical trial phases [38]. Nonetheless, Axl TKIs have increased clinical off-target toxicity and drug resistance [114,115].…”

“…Nonetheless, Axl TKIs have increased clinical off-target toxicity and drug resistance [114,115]. Nucleotide aptamers and mAbs are emerging therapy with higher affinity and specificity, and lower toxicity and drug resistance [92,[116][117][118], although their application is currently at preclinical stages [38]. Other than the transmembrane form, Axl can also exist in a soluble form once it is cleaved in the extracellular domain.…”