c-Mer proto-oncogene tyrosine kinase (MERTK) and AXL receptor tyrosine kinase (AXL) (MERTK/AXL)

MERTK (c-Mer proto-oncogene tyrosine kinase) and AXL (AXL receptor tyrosine kinase) are members of the TAM family of receptor tyrosine kinases, which also includes TYRO3 [1, 12]. These receptors are characterized by an extracellular domain containing two immunoglobulin-like domains and two fibronectin type III domains, and an intracellular tyrosine kinase domain [12, 17]. Their primary physiological role involves the clearance of apoptotic cells, a process known as efferocytosis, and the negative regulation of the innate immune response to prevent chronic inflammation [7, 9]. In many cancers, MERTK and AXL are overexpressed or constitutively active, contributing to tumor progression by promoting cell survival, migration, and resistance to chemotherapy or targeted therapies [1, 14]. They also play a significant role in the tumor microenvironment by polarizing macrophages toward an immunosuppressive M2-like phenotype and inhibiting natural killer cell activity [2, 16]. Consequently, dual inhibition of MERTK and AXL has emerged as a potent therapeutic strategy to simultaneously induce tumor cell apoptosis and stimulate a robust anti-tumor immune response [6, 11]. Several small-molecule inhibitors and monoclonal antibodies targeting these receptors are currently in clinical and preclinical development [2, 8].

Other names

Merc-MerMerTKTyro12UFOJTK11Tyro7TAM family

Inhibition of the intracellular tyrosine kinase domain, blocking autophosphorylation and downstream signaling pathways such as PI3K/AKT and MAPK/ERK, while simultaneously modulating the innate immune response by reversing M2 macrophage polarization.