Platelet-derived growth factor receptor alpha (PDGFRA) V561D mutant (PDGFRA V561D)

The Platelet-derived growth factor receptor alpha (PDGFRA) V561D mutant is a constitutively active receptor tyrosine kinase resulting from a point mutation in the juxtamembrane domain [1, 10]. This mutation, located in exon 12, disrupts the receptor's auto-inhibitory mechanism, leading to ligand-independent signaling [13, 16]. It is a significant oncogenic driver in a subset of gastrointestinal stromal tumors (GISTs), particularly those occurring in the stomach [10, 16]. Activation of the V561D mutant triggers downstream pathways such as PI3K/AKT and RAS/MAPK, which promote uncontrolled cell proliferation and survival [10, 16]. Clinically, this specific mutant is notable for its high sensitivity to the tyrosine kinase inhibitor imatinib, which is the standard first-line therapy [1, 3, 15]. Other drugs, including sunitinib, regorafenib, and avapritinib, also show activity against this target, providing options for subsequent lines of treatment [4, 9, 12]. However, long-term therapy can be challenged by the development of secondary resistance mutations in the kinase domain [1, 17]. Monitoring for these mutations and managing drug-specific toxicities, such as edema or cognitive effects, are essential components of patient care [17].

Other names

CD140APDGFR-alphaPlatelet-derived growth factor receptor 1PDGFR-α

Tyrosine kinase inhibition via competitive binding to the ATP-binding site, preventing downstream phosphorylation and signaling [9, 17].