AXL and MER receptor tyrosine kinases (AXL/MERTK)

AXL and MER (MERTK) are members of the TAM family of receptor tyrosine kinases, which are essential for regulating immune homeostasis and cell survival (UniProt P30530, Q12866). These receptors are primarily activated by the ligands GAS6 and Protein S, which induce receptor dimerization and autophosphorylation to trigger downstream pathways like PI3K/AKT and MAPK/ERK (PMID: 25264244). In many cancers, AXL and MERTK are overexpressed, driving tumor progression, metastasis, and resistance to conventional therapies through the induction of the epithelial-to-mesenchymal transition (EMT) (PMID: 21135154). Furthermore, they function as innate immune checkpoints by facilitating efferocytosis—the clearance of apoptotic cells—and suppressing pro-inflammatory cytokine production in the tumor microenvironment (PMID: 28864478). This dual role in promoting tumor cell fitness and extrinsic immune evasion makes them highly attractive therapeutic targets. Current drug development efforts focus on small molecule kinase inhibitors, monoclonal antibodies, and antibody-drug conjugates, with several agents currently in clinical trials for solid tumors and hematological malignancies (ClinicalTrials.gov). Beyond oncology, these receptors are also investigated for their roles in viral entry and fibrotic diseases (PMID: 32661320).

Other names

TAM receptorsTyro3-Axl-Mer familyUFOc-MerTyrosine-protein kinase receptor UFOc-mer proto-oncogene tyrosine kinaseSTK kinase

Inhibition of the intracellular tyrosine kinase domain to prevent autophosphorylation and downstream signaling through PI3K/AKT, MAPK/ERK, and JAK/STAT pathways (PMID: 25264244). Additionally, targeting these receptors can block GAS6-mediated signaling, inhibit efferocytosis to promote a pro-inflammatory tumor microenvironment, and reverse epithelial-to-mesenchymal transition (EMT) (PMID: 28864478).