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

The Proto-oncogene tyrosine-protein kinase receptor Ret (RET) is a transmembrane receptor tyrosine kinase essential for the development of the enteric nervous system and renal organogenesis (UniProt P07949; NCBI Gene 5979). It is activated by ligands of the glial cell line-derived neurotrophic factor (GDNF) family, which require a GFRα co-receptor to facilitate RET dimerization and autophosphorylation (UniProt P07949; StatPearls). This activation triggers downstream signaling pathways, including RAS/MAPK, PI3K/AKT, and PLCγ, which regulate cell survival, proliferation, and differentiation (UniProt P07949). In humans, germline or somatic mutations in the RET gene are primary drivers of medullary thyroid carcinoma and multiple endocrine neoplasia type 2 (MEN2), while RET fusions are frequently observed in papillary thyroid cancer and non-small cell lung cancer (NCBI Gene 5979; StatPearls). Historically, RET-driven cancers were treated with multi-kinase inhibitors like cabozantinib, but the development of highly selective RET inhibitors such as selpercatinib and pralsetinib has significantly improved clinical outcomes (FDA Labels; PubMed). These targeted therapies specifically block the ATP-binding site of the RET kinase domain, effectively inhibiting oncogenic signaling (FDA Labels; StatPearls). Patient selection for these drugs relies on the identification of specific RET alterations through molecular biomarkers like next-generation sequencing (FDA Labels).

Other names

RET proto-oncogeneCadherin family member 12CDHF12CDHR16HSCR1MEN2AMEN2BMTC1PTCRET51

Selective or multi-kinase inhibition of the RET tyrosine kinase domain to block downstream signaling pathways such as RAS/MAPK and PI3K/AKT.