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

Proto-oncogene tyrosine-protein kinase receptor Ret (RET) is a transmembrane receptor tyrosine kinase that plays a critical role in the development of the enteric nervous system and renal organogenesis [UniProt: P07949]. 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 subsequent autophosphorylation of its intracellular kinase domain [PMID: 29335524]. This phosphorylation initiates several intracellular signaling cascades, including the MAPK, PI3K/Akt, and STAT3 pathways, which regulate cell proliferation, survival, and differentiation [PMID: 30103373]. In oncology, RET is a well-validated driver; gain-of-function mutations are frequently associated with medullary thyroid cancer, while RET gene fusions are prevalent in papillary thyroid cancer and a subset of non-small cell lung cancers [PMID: 32853445]. Modern therapeutic interventions utilize highly selective RET inhibitors that bind to the ATP-binding pocket of the kinase domain to block oncogenic signaling [PMID: 32853445]. These selective agents, such as selpercatinib and pralsetinib, have largely superseded older multi-kinase inhibitors due to their superior potency and reduced off-target toxicity [FDA: Retevmo Label].

Other names

Rearranged during transfectionRET proto-oncogeneCadherin family member 12CDHF12RET51RET-ELE1RET kinase domain

Small molecule inhibition of the intracellular kinase domain, preventing ATP binding and subsequent autophosphorylation and downstream signaling [PMID: 32853445].