Tyrosine-protein kinase KIT and Platelet-derived growth factor receptor alpha (KIT and PDGFRA)

Tyrosine-protein kinase KIT and platelet-derived growth factor receptor alpha (PDGFRA) are both type III receptor tyrosine kinases composed of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular kinase domain. KIT, encoded by the c-KIT gene, is crucial for the development of hematopoietic cells, melanocytes, and gametes through binding stem cell factor (SCF), triggering dimerization and phosphorylation cascades that mediate cell growth and survival. PDGFRA binds platelet-derived growth factor and activates similar downstream signaling pathways involved in cell proliferation and tissue growth. Gain-of-function mutations in either receptor, particularly KIT or PDGFRA (e.g., D842V), drive the majority of GISTs, often leading to constitutive activation of kinase activity independent of ligand binding. Both targets remain a major focus for drug development in oncology, but significant clinical challenges exist due to the emergence of therapy-resistant clones and overlapping signaling pathways.

Other names

c-KITCD117Mast/stem cell growth factor receptor (SCFR)PDGFRαPlatelet-derived growth factor receptor alpha

Most drugs are tyrosine kinase inhibitors (TKIs) that block ATP-binding or allosteric sites, thereby inhibiting kinase activation and downstream signal transduction. Some drugs selectively target resistance-conferring mutations in activation loop or ATP-binding domain, e.g., D842V in PDGFRA. Combination therapies may target polyclonal resistance by targeting multiple RTKs simultaneously.