Four decades of the RET gene: From discovery to tumor-agnostic therapy

The physiological and disease-related roles of the Rearranged during Transfection (RET) gene have been extensively studied since its discovery four decades ago. RET encodes a receptor tyrosine kinase whose ligands are members of the glial cell line-derived neurotrophic factor (GDNF) family. Unlike other receptor tyrosine kinase ligands, GDNF family ligands (GFLs) do not bind to RET directly; instead, RET requires GDNF family receptor αs (GFRαs) as coreceptors for their binding. The resulting GFL/GFRα/RET ternary complex plays physiologically crucial roles in developing some organ systems. RET alterations cause various human cancers and developmental disorders. Gene rearrangements occur in 5–20 % of papillary thyroid carcinoma, 1–2 % of non-small cell lung carcinoma, and <1 % of other solid cancers. Germline and somatic RET point mutations have been detected in almost all multiple endocrine neoplasia type 2 families and 40–70 % of sporadic medullary thyroid carcinoma. Moreover, RET loss-of-function mutations or deletions cause Hirschsprung's disease. Selective RET kinase inhibitors have recently shown remarkable progress for the treatment of advanced non-small cell lung and thyroid cancers. As RET alterations occur across multiple tumor types, RET inhibitor development is enabling a new paradigm of tumor-agnostic therapies. This review highlights clinical efficacy of selective RET inhibitors.