Growth arrest-specific protein 6–AXL receptor tyrosine kinase signaling pathway (GAS6-AXL) (GAS6-AXL)

The Growth arrest-specific protein 6 (GAS6)–AXL receptor tyrosine kinase signaling pathway is a critical mediator of tumor progression, immune evasion, and therapeutic resistance [PubMed: 28337902]. AXL, a member of the TAM (Tyro3, Axl, MerTK) receptor family, is activated upon binding its primary ligand GAS6, leading to the activation of downstream survival pathways such as PI3K/AKT and MAPK/ERK [UniProt: P30530]. This signaling axis is a hallmark of the epithelial-to-mesenchymal transition (EMT), a process that allows cancer cells to acquire invasive properties and survive the selective pressure of chemotherapy and targeted therapies [PubMed: 30228157]. In addition to its cell-intrinsic roles, the GAS6-AXL axis functions as an immune checkpoint by suppressing the activation of innate immune cells and promoting an anti-inflammatory environment that shields tumors from immune surveillance [PubMed: 27141351]. Clinically, AXL overexpression is associated with poor prognosis across a wide range of malignancies, including non-small cell lung cancer, acute myeloid leukemia, and ovarian cancer [PubMed: 25213834]. Therapeutic strategies targeting this pathway aim to reverse drug resistance and enhance the efficacy of immuno-oncology agents. Current drug candidates include selective AXL inhibitors like bemcentinib, multi-kinase inhibitors such as cabozantinib, and GAS6-sequestering decoy receptors like batiraxcept [ClinicalTrials.gov]. By inhibiting this pathway, researchers hope to block metastasis and restore the sensitivity of tumors to standard-of-care treatments.

Other names

GAS6/AXL axisTAM signaling pathwayAXL-GAS6 signalingGAS6-AXL pathwayAXL signaling pathway

The pathway is targeted through several distinct modalities: small-molecule tyrosine kinase inhibitors (TKIs) that bind to the intracellular ATP-binding pocket of AXL to block downstream signaling; monoclonal antibodies that bind the extracellular domain of AXL to induce receptor internalization or block ligand binding; and soluble decoy receptors (ligand traps) that sequester circulating GAS6, thereby preventing its interaction with membrane-bound AXL [PubMed: 28337902, PubMed: 30228157].