Proto-oncogene tyrosine-protein kinase receptor Ret (V804L mutant) (RET V804L)

The RET V804L mutant refers to a specific alteration in the Rearranged during Transfection (RET) proto-oncogene, which encodes a receptor tyrosine kinase critical for the development of the nervous and renal systems (1.1.3, 1.5.2). The V804L substitution occurs at the gatekeeper position within the ATP-binding pocket of the kinase domain, leading to constitutive, ligand-independent activation of downstream signaling pathways such as MAPK/ERK and PI3K/AKT (1.1.1, 1.3.1). This mutation is frequently associated with medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2 (MEN2), where it drives oncogenesis and tumor progression (1.1.2, 1.5.2). Historically, the V804L mutation has been a significant therapeutic challenge because it confers resistance to first-generation multikinase inhibitors, such as vandetanib and cabozantinib, by creating steric hindrance that prevents drug binding (1.3.1, 1.4.1). However, second-generation selective RET inhibitors, including selpercatinib and pralsetinib, have been engineered to circumvent this gatekeeper mutation, providing potent and durable clinical responses for patients harboring this specific genetic alteration (1.2.2, 1.3.4).

Other names

RET V804LRET p.Val804LeuGatekeeper mutation V804LRearranged during transfection V804LCadherin family member RET V804L

ATP-competitive inhibition of the RET receptor tyrosine kinase domain