Tyrosine-protein kinase receptor TYRO3 (TYRO3), Tyrosine-protein kinase receptor UFO (AXL), Tyrosine-protein kinase receptor Mer (MERTK), and Vascular endothelial growth factor receptor 2 (VEGFR2) (TYRO3/AXL/MERTK/VEGFR2)

The TYRO3/AXL/MERTK/VEGFR2 target profile represents a specific cluster of receptor tyrosine kinases (RTKs) that are frequently co-targeted in oncology to address both tumor growth and the immune microenvironment (Graham et al., 2014, Nature Reviews Cancer). The TAM family, consisting of TYRO3, AXL, and MERTK, plays a pivotal role in regulating innate immunity and the clearance of apoptotic cells, a process known as efferocytosis (UniProt P32916, P30530, Q12866). In the context of cancer, TAM receptors are often overexpressed, promoting tumor cell survival, epithelial-mesenchymal transition, and an immunosuppressive microenvironment. VEGFR2 is the primary mediator of angiogenesis, facilitating the development of the tumor vasculature necessary for growth and metastasis (UniProt P35968). Drugs targeting this combination, such as sitravatinib, are designed to inhibit both the proliferative signals of the TAM family and the angiogenic signals of VEGFR2 (Patwardhan et al., 2016, JCI Insight). This dual action helps to convert the tumor microenvironment from an immunosuppressive 'cold' state to an immune-active 'hot' state. Clinical applications of these inhibitors often focus on patients who have developed resistance to prior therapies, including immune checkpoint inhibitors. By blocking these pathways, these agents aim to reduce the presence of myeloid-derived suppressor cells and enhance the infiltration of cytotoxic T cells.

Other names

TAM/VEGFR2TAM family and VEGFR2Sitravatinib target profile

ATP-competitive inhibition of the intracellular kinase domains of TYRO3, AXL, MERTK, and VEGFR2, which prevents receptor autophosphorylation and blocks downstream signaling pathways including PI3K/AKT, MAPK/ERK, and PLC-gamma (Patwardhan et al., 2016, JCI Insight).