AXL in cancer: a modulator of drug resistance and therapeutic target

Abstract

AXL is a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases family (RTKs), and its abnormal expression has been linked to clinicopathological features and poor prognosis of cancer patients. There is mounting evidence supporting AXL's role in the occurrence and progression of cancer, as well as drug resistance and treatment tolerance. Recent studies revealed that reducing AXL expression can weaken cancer cells' drug resistance, indicating that AXL may be a promising target for anti-cancer drug treatment. This review aims to summarize the AXL's structure, the mechanisms regulating and activating it, and its expression pattern, especially in drug-resistant cancers. Additionally, we will discuss the diverse functions of AXL in mediating cancer drug resistance and the potential of AXL inhibitors in cancer treatment.

Keywords: AXL; Cancer; Drug resistance; Molecular mechanisms; Target therapy.

Fig. 1

The structure of AXL and GAS6. A The AXL protein comprises an intracellular domain, single helix transmembrane region, two fibronectin type III (FNIII) domains, and two immunoglobulin (IG)-like domains. On the other hand, GAS6 consists of a γ-carboxyglutamic acid (GLA) domain, a loop region, four epidermal growth factor (EGF)-like repeats, and two globular laminin G like (LG) domains. In Figure B and C, we can observe the interaction between AXL and GAS6, front both the front and top sides respectively, as visualized in the Protein Data Bank (PDB) with the identifier 2C5D

Fig. 2

The regulation of AXL. A Expression of AXL is regulated by various transcription factors. B AXL undergoes post-transcriptional regulation. C The protein level of AXL is regulated in the post-translation stage

Fig. 3

Signal pathways mediated by AXL in the occurrence and development of cancer. AXL play a crucial role in the occurrence and development of cancer through various signal pathways

Fig. 4

AXL-mediated epithelial–mesenchymal transition (EMT) in drug-resistant cancer. AXL is known to activate EMT transcription factors through three pathways to promote EMT transformation and drug resistance of cancer cells. These pathways include AKT/GSK-3β/β-catenin, TGF-β/Smad3, and PI3K/AKT/HIF-1α

Fig. 5

AXL affect DNA damage and DNA damage response (DDR) in drug-resistant cancer. DNA damage and repair are dynamic processes that require a delicate balance. AXL plays a crucial role in maintaining this balance by not only inhibiting DNA damage but also participating in multiple processes of DNA repair, such as DNA damage response (DDR), metabolic reprogramming, cell cycle arrest, and apoptosis

Fig. 6

AXL-mediated immunosuppression in drug-resistant cancer. AXL plays a key role in mediating immunosuppression through both intrinsic shaping of cancer cells and extrinsic modification of microenvironment surrounding tumors