Platelet-derived growth factor receptor alpha D842V (PDGFRα D842V)

Platelet-derived growth factor receptor alpha (PDGFRα) D842V is a specific somatic point mutation in the activation loop of the PDGFRα protein, a member of the receptor tyrosine kinase family (UniProt P16234). This mutation involves the substitution of aspartic acid with valine at position 842, which results in the constitutive, ligand-independent activation of the kinase domain (Corless et al., 2005). In the context of oncology, the D842V mutation is a primary oncogenic driver in approximately 5% to 10% of gastrointestinal stromal tumors (GIST) (NIH/NCI). Historically, this specific variant was characterized by its profound resistance to standard-of-care tyrosine kinase inhibitors such as imatinib and sunitinib, posing a significant clinical challenge (Heinrich et al., 2020). The therapeutic landscape changed with the introduction of avapritinib, a highly selective inhibitor designed to target the active conformation of the PDGFRα D842V mutant (FDA, 2020). By binding to the kinase, these drugs inhibit downstream signaling pathways like PI3K/AKT and MAPK, effectively suppressing tumor growth. Consequently, testing for the D842V mutation has become a standard biomarker-driven approach for patient selection in GIST management (NCCN Guidelines).

Other names

PDGFRA D842VPlatelet-derived growth factor receptor alpha exon 18 D842V mutationCD140A D842VPDGFR-alpha D842V

Avapritinib acts as a potent and selective type I kinase inhibitor that binds to the active conformation of the PDGFRα D842V mutant protein, thereby blocking ATP binding and inhibiting the constitutive phosphorylation that drives oncogenic signaling (Evans et al., 2017; Heinrich et al., 2020).