Platelet-derived growth factor receptor alpha T674I (PDGFRα T674I)

Platelet-derived growth factor receptor alpha (PDGFRα) T674I is a clinically significant mutant form of the PDGFRα protein (UniProt: P16234). The T674I substitution occurs at the gatekeeper residue within the ATP-binding pocket of the kinase domain, which is a critical site for the binding of many tyrosine kinase inhibitors (TKIs) (PubMed: 15692071). This specific mutation is most frequently identified in patients with FIP1L1-PDGFRA-positive chronic eosinophilic leukemia (CEL) or hypereosinophilic syndrome (HES) who have developed resistance to imatinib therapy (PubMed: 12660387). Biologically, the mutation maintains the receptor in a constitutively active state, driving uncontrolled cell proliferation and survival through downstream signaling pathways like PI3K/AKT and MAPK/ERK. Because the bulky isoleucine residue sterically hinders the binding of first-generation inhibitors like imatinib and nilotinib, this target represents a major therapeutic challenge. Research focuses on next-generation TKIs, such as ponatinib and crenolanib, which are designed to overcome the steric hindrance posed by the T674I gatekeeper mutation (PubMed: 22517901).

Other names

PDGFRA T674ICD140A T674IPlatelet-derived growth factor receptor 1 T674IFIP1L1-PDGFRA T674IPDGFR-alpha T674I

Inhibition of the tyrosine kinase activity by competing with ATP binding in the catalytic domain of the mutated receptor to block downstream oncogenic signaling.