Multi-targeted receptor tyrosine kinase (RTK) (Multi-RTK)

This target profile represents a cluster of receptor tyrosine kinases (RTKs) that play pivotal roles in tumor angiogenesis, lymphangiogenesis, and the maintenance of the tumor microenvironment (PubMed: 16434533). The group includes Vascular endothelial growth factor receptors (VEGFR-1, -2, -3), Platelet-derived growth factor receptors (PDGFR-α, -β), KIT proto-oncogene receptor tyrosine kinase (c-Kit), Fibroblast growth factor receptors (FGFR-1, -3), and Colony stimulating factor 1 receptor (c-fms/CSF1R) (UniProt: P17948, P16234, P10721). These receptors are essential for the proliferation and migration of endothelial cells, pericytes, and fibroblasts, which are necessary for the formation of new blood vessels and the development of tumor stroma (PubMed: 24658454). In many cancers, these pathways are overactivated through ligand overexpression or activating mutations, driving tumor growth and metastasis (PubMed: 21854171). Multi-kinase inhibitors (MKIs) are designed to bind to the intracellular ATP-binding sites of these receptors, effectively blocking downstream signaling cascades like the MAPK and PI3K pathways (PubChem: Sunitinib). By targeting multiple receptors simultaneously, these drugs can circumvent resistance mechanisms that tumors use to bypass single-pathway inhibition (PubMed: 22507837). Clinically, these inhibitors are used to treat a variety of malignancies, including renal cell carcinoma, gastrointestinal stromal tumors, and hepatocellular carcinoma (FDA: Sutent, Stivarga). However, the broad inhibition of these physiologically important kinases leads to characteristic systemic toxicities, such as hypertension, hand-foot skin reaction, and fatigue (StatPearls: Tyrosine Kinase Inhibitors).

Other names

VEGFR/PDGFR/FGFR/KIT/CSF1R kinase clusterAngiogenic receptor tyrosine kinasesMulti-kinase inhibitor targetsReceptor tyrosine kinase family

Inhibition of the intracellular kinase domain of multiple receptor tyrosine kinases by competing with adenosine triphosphate (ATP) for binding, thereby blocking downstream signaling cascades such as the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways (PubChem: Sunitinib; PubMed: 16434533).