Proto-oncogene tyrosine-protein kinase receptor Ret (RET) V804M mutant (RET V804M)

The Proto-oncogene tyrosine-protein kinase receptor Ret (RET) is a transmembrane protein essential for the development of the nervous and genitourinary systems, where it mediates signaling for cell growth, survival, and differentiation upon binding to glial cell line-derived neurotrophic factor (GDNF) family ligands (UniProt, 2024). The V804M mutation is a specific point mutation in the kinase domain where valine is replaced by methionine at position 804, acting as a "gatekeeper" residue (NIH, 2019). This mutation is frequently associated with hereditary medullary thyroid cancer (MTC) and multiple endocrine neoplasia type 2A (MEN2A), often presenting with a later onset and more indolent clinical course than other RET mutations (NIH, 2018). Crucially, V804M confers resistance to first-generation multikinase inhibitors like vandetanib and cabozantinib by sterically blocking their binding to the ATP-binding pocket (ASCO, 2019). However, next-generation selective RET inhibitors, such as selpercatinib and pralsetinib, have been specifically engineered to overcome this resistance, demonstrating high efficacy in patients harboring the V804M mutation (NIH, 2024). Monitoring of these patients typically involves tracking serum calcitonin and carcinoembryonic antigen (CEA) levels as biomarkers of disease progression (NIH, 2020).

Other names

RETCDHF12CDHR16PTCRET51Proto-oncogene c-Ret

Selective inhibition of the RET kinase domain by competing with ATP binding, thereby blocking downstream signaling pathways such as MAPK/ERK and PI3K/AKT (NIH, 2024).