Rearranged during transfection receptor tyrosine kinase (RET) (RET)

The Rearranged during transfection (RET) receptor tyrosine kinase is a transmembrane protein that plays a critical role in the development of the enteric nervous system and the kidneys (UniProt: P07949). Under physiological conditions, RET is activated by the binding of glial cell line-derived neurotrophic factor (GDNF) family ligands in conjunction with GFRα co-receptors, which triggers intracellular signaling pathways such as RAS/MAPK and PI3K/Akt to promote cell survival, differentiation, and proliferation (PubMed: 29045895). In the context of oncology, RET acts as a powerful oncogenic driver through two primary mechanisms: activating point mutations, which are characteristic of medullary thyroid carcinoma, and chromosomal rearrangements that create RET fusions, commonly observed in non-small cell lung cancer and papillary thyroid cancer (NIH: NBK562223). These alterations lead to constitutive, ligand-independent activation of the kinase domain, fueling tumor growth and progression. Therapeutic strategies have evolved from broad-spectrum multi-kinase inhibitors to highly potent and selective RET inhibitors like selpercatinib and pralsetinib, which are designed to target both wild-type and various mutant or fusion forms of the protein (PubMed: 32846060). These selective agents offer improved efficacy and a more favorable safety profile compared to older therapies by reducing off-target inhibition of other kinases like VEGFR2 (PubMed: 32846061).

Other names

Proto-oncogene tyrosine-protein kinase receptor RetCadherin family member 12CDHF12RET51RET-ELE1HSCR1MEN2AMEN2BMTC1PTC

Selective or multi-kinase inhibition of the RET tyrosine kinase domain, preventing ATP binding and subsequent autophosphorylation and downstream oncogenic signaling (PubMed: 32846060).