AXL signaling in cancer: from molecular insights to targeted therapies

Abstract

AXL, a member of the TAM receptor family, has emerged as a potential target for advanced-stage human malignancies. It is frequently overexpressed in different cancers and plays a significant role in various tumor-promoting pathways, including cancer cell proliferation, invasion, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, DNA damage response, acquired therapeutic resistance, immunosuppression, and inflammatory responses. Beyond oncology, AXL also facilitates viral infections, including SARS-CoV-2 and Zika highlighting its importance in both cancer and virology. In preclinical models, small-molecule kinase inhibitors targeting AXL have shown promising anti-tumorigenic potential. This review primarily focuses on the induction, regulation and biological functions of AXL in mediating these tumor-promoting pathways. We discuss a range of therapeutic strategies, including recently developed small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and antibody-drug conjugates (ADCs), anti-AXL-CAR, and combination therapies. These interventions are being examined in both preclinical and clinical studies, offering the potential for improved drug sensitivity and therapeutic efficacy. We further discuss the mechanisms of acquired therapeutic resistance, particularly the crosstalk between AXL and other critical receptor tyrosine kinases (RTKs) such as c-MET, EGFR, HER2/HER3, VEGFR, PDGFR, and FLT3. Finally, we highlight key research areas that require further exploration to enhance AXL-mediated therapeutic approaches for improved clinical outcomes.

Fig. 1

Structure and activation mechanisms of the TYRO3, AXL, and MERTK (TAM) receptors. a The TAM receptors and ligands share closely related structures. The structure of growth arrest-specific protein 6 (GAS6) and vitamin K-dependent protein S (PROS1) comprises a γ-carboxyglutamic acid (GLA) domain, a loop region, four epidermal growth factor-like (EGF-like) repeats, and two C-terminal globular laminin G-like (LG) domains. TAM receptors consist of two immunoglobulin-like (Ig) domains, two fibronectin III (FNIII) repeat domains, and a kinase domain. GAS6 binds to all three receptors, while PROS1 binds to MERTK and TYRO3, but not to AXL. The decreasing width of the arrows indicates a reduction in receptor activation strength by the ligands, reflecting their relative affinities. b Ligand-Dependent Activation: Binding of GAS6 to AXL leads to receptor activation. Optimal activation requires PtdSer (phosphatidylserine) on the opposed cell membrane, which binds to the GLA domain of the ligand. c Ligand-Independent Activation: Various factors in the tumor microenvironment can activate AXL in a ligand-independent manner. d Homophilic Interaction: Activation can occur through interaction between AXL monomers on neighboring cells. e Heterophilic Activation: AXL can also be activated heterophilically with non-TAM receptors. Activation of AXL through these mechanisms results in autophosphorylation of intracellular tyrosine residues, initiating signaling pathways that promote tumor proliferation, invasion, migration, angiogenesis, drug resistance, and immune evasion

Fig. 2

AXL regulates multiple biological processes in cancer. AXL is pivotal in regulating several key biological processes in cancer. Upon binding to its ligand, GAS6, AXL becomes activated, triggering downstream signaling pathways that promote cancer cell proliferation, survival, migration, invasion, epithelial-to-mesenchymal transition (EMT), angiogenesis, stem cell maintenance, and immune suppression or evasion

Fig. 3

AXL induces acquired therapeutic resistance by modulating DNA damage and repair processes. AXL induces acquired therapeutic resistance by modulating DNA damage and DNA damage response processes. AXL plays a vital role in maintaining this equilibrium by inhibiting DNA damage and regulating various DNA damage response mechanisms leading to error-prone DNA replication, genomic instability and inhibition of cell death mechanisms. (HR- Homologous Recombination, NHEJ- Non-Homologous End Joining)

Fig. 4

AXL-mediated phenotypic changes in cancer cells induce therapeutic resistance. AXL promotes epithelial-to-mesenchymal transition (EMT) and therapeutic resistance by inducing several EMT transcription factors, such as Snail, Slug, Smad-3, β-catenin, and TWIST1, as well as markers like MMP9, ZEB1, and Vimentin. The TGF-β/Smad-4/YAP pathway is reported to upregulate AXL expression, facilitating these phenotypic changes in cancer cells

Fig. 5

AXL-directed therapeutic resistance via activation of bypass signaling. a Under basal conditions, AXL is shed through the action of ADAM10/17. b In bypass signaling, MAPK inhibition decreases sheddase activity by enhancing the association between TIMP1 and ADAM10/17. This inhibition boosts mitogenic signaling through bypass kinases like JNK, leading to sustained secondary tolerance to EGFR TKIs

Fig. 6

AXL alters glucose metabolism to develop acquired resistance in cancer cells. AXL-GAS6 signaling promotes glycolysis through multiple pathways, reducing sensitivity to cytotoxic stress and fostering chemoresistance. AXL-mediated PI3K/Akt signaling activates glycolysis. After AXL phosphorylates TNS2 at Y483, TNS2 becomes more stable and disengages from IRS-1. The overexpression of GLUT4 and PDK1, resulting from AXL/TNS2/IRS-1 crosstalk, enhances related metabolism. Additionally, AXL phosphorylates PKM2 at Y105, reducing its ability to bind phosphoenolpyruvate and further promoting glycolysis

Fig. 7

AXL crosstalk with different receptor tyrosine kinases promotes drug resistance. AXL interacts with several oncogenic receptor tyrosine kinases (RTKs), such as TYRO3 and MERTK, and heterodimerizes with several non-TAM receptors like EGFR, MET, PDGFR, and FLT3. It also forms dimers with HER2/3. These interactions activate downstream signaling pathways, leading to cancer cell proliferation, metastasis, angiogenesis, and drug resistance. Multiple tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), and antibody–drug conjugates (ADCs) shown have potential in overcoming therapeutic resistance in various cancers