Platelet-derived growth factor receptor alpha (PDGFRA) D842V mutant (PDGFRA D842V)

The Platelet-derived growth factor receptor alpha (PDGFRA) D842V mutant is a specific oncogenic variant of the PDGFRA protein, which belongs to the type III receptor tyrosine kinase family [1, 2]. This mutation occurs in exon 18 and involves the substitution of aspartic acid with valine at position 842 in the activation loop of the kinase domain [1, 4]. This alteration stabilizes the receptor in its active conformation, leading to constitutive, ligand-independent signaling through the PI3K-AKT-mTOR, RAS-MAPK, and JAK-STAT pathways [2, 3]. Clinically, the D842V mutation is found in approximately 5-10% of gastrointestinal stromal tumors (GISTs) and is notorious for conferring primary resistance to standard tyrosine kinase inhibitors such as imatinib and sunitinib [1, 8]. Avapritinib was specifically developed to target this mutant and is currently the only FDA-approved therapy providing durable clinical responses for patients with this genomic profile [11]. Management of patients with this target requires precise molecular testing to avoid ineffective treatment with conventional TKIs and to monitor for specific side effects like cognitive dysfunction [2, 11]. The mutation's location in the activation loop prevents the binding of inhibitors that require the inactive conformation, necessitating the use of type I inhibitors [1, 8]. Research continues into overcoming secondary resistance that may emerge during avapritinib treatment [7, 8].

Other names

PDGFRA exon 18 D842V mutationD842V-mutant PDGFRAAsp842Val mutant of Platelet-derived growth factor receptor alphaPDGFRA D842V

Selective ATP-competitive inhibition of the activated kinase conformation, preventing downstream oncogenic signaling [1, 11].