Molecular Classification
Receptor tyrosine kinase (RTK), Type XI RTKs: TAM (TYRO3, AXL, and MER-TK) receptor family, Cell surface receptor
Other Names
Tyrosine-protein kinase receptor UFO, Anexelekto, Ark, Tyro7, UFO
Disease Roles
Cancer (including lung, breast, pancreatic, ovarian, colon cancer, melanoma, hematological malignancies such as leukemia and lymphoma)Drug resistance in cancer therapyMetastasis and tumor progression

AXL receptor tyrosine kinase Overview

AXL receptor tyrosine kinase is a cell surface protein encoded by the *AXL* gene located at chromosome 19q13.2. It belongs to the TAM family of type XI receptor tyrosine kinases along with TYRO3 and MERTK. Structurally distinct among RTKs due to its extracellular region containing two immunoglobulin-like domains and two fibronectin type III repeats coupled with an intracellular tyrosine kinase domain,[1][4] it primarily binds growth arrest-specific protein 6 (GAS6) as its high-affinity ligand.[5] Upon ligand binding and dimerization/autophosphorylation events,[5] it activates downstream signaling pathways including PI3K/AKT that regulate cell survival/proliferation/migration while suppressing apoptosis.[5] Clinically significant for its overexpression/activation across multiple solid tumors and hematologic malignancies,[1][7] elevated AXL drives tumor progression via promoting epithelial-mesenchymal transition (EMT), metastasis formation,[7][9] drug resistance mechanisms,[2][10] angiogenesis modulation,[9] immune evasion,[1], fibrosis development,[1], as well as facilitating viral entry into host cells.[1] Therapeutically actionable through small molecule inhibitors like bemcentinib/BGB324/R428 currently under clinical investigation for various cancers; other strategies include monoclonal antibodies or agents disrupting GAS6/AXL interaction.[9] In summary: The "AXL receptor tyrosine kinase" is a validated therapeutic target implicated broadly across oncology—and increasingly other disease areas—due to its central role at the intersection of oncogenic signaling networks governing tumor aggressiveness/drug resistance/metastatic potential/immunomodulation/fibrosis/infection biology.[1][4][5][7][10]

Mechanism of Action

Drugs targeting this molecule typically act by inhibiting its tyrosine kinase activity—either through ATP-binding site competition or by blocking ligand binding—thereby preventing downstream signaling involved in cell survival, proliferation, migration/invasion, drug resistance mechanisms in cancer cells[9][10]. Some approaches use decoy receptors to trap the ligand GAS6 or vitamin K antagonists to reduce GAS6-mediated activation[9].

Biological Functions

Signal transduction
Cell survival
Cell proliferation
Cell migration and adhesion
Suppression of apoptosis
Immune regulation (including macrophage activation and phagocytosis)

Disease Associations

Cancer (including lung, breast, pancreatic, ovarian, colon cancer, melanoma, hematological malignancies such as leukemia and lymphoma)
Drug resistance in cancer therapy
Metastasis and tumor progression
Fibrotic diseases (e.g., liver fibrosis)
Viral infection facilitation (e.g., Zika virus, SARS-CoV‑2)

Safety Considerations

  • Potential safety concerns include effects on normal immune function due to the role of TAM receptors in immune regulation. However, genetic deletion or pharmacological inhibition of AXL appears well tolerated in preclinical models. Off-target effects may occur with less selective inhibitors. The impact on hemostasis should be monitored due to roles of TAM kinases in coagulation pathways[9][10].

Interacting Drugs

Bemcentinib (BGB324/R428), a highly specific small molecule inhibitor of AXL[9].
Other broad-spectrum kinase inhibitors with activity against AXL are also under study[9].
Monoclonal antibodies targeting AXL are in development[9].

Associated Biomarkers

Biomarker
AXL expression is being explored as a prognostic biomarker for poor outcome in several cancers; high levels correlate with aggressive disease and therapy resistance. It may also serve as a predictive biomarker for response to targeted therapies or immunotherapies involving the GAS6/AXL axis[1][5][7].