RET (rearrangement during transfection) is a tyrosine kinase receptor that, when fused with a partner molecule, activates oncogenic activity and promotes unchecked cellular proliferation.1 Typically, RET is present on the surface of tissues in the peripheral nervous system, adrenal medulla, kidneys, and thyroid C-cells, among other tissues, and is important in the development of the neural crest, kidney, and male germ cells.2
The RET receptor contains 3 domains—extracellular domain, transmembrane domain, and intracellular tyrosine kinase domain—and activation of RET requires indirect ligand binding to form a multimeric protein complex.3 These ligands belong to the glial-derived neurotropic factor family and bind to a glial-derived neurotropic factor family receptor-alpha.4 This complex then mediates RET homodimerization and autophosphorylation, which activates RET.4 Once activated, RET engages intracellular signaling pathways, including the mitogen‐activated protein kinase, PI3K/AKT, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways.1 Activation of these pathways results in cell proliferation, motility, and survival.3 In the absence of a ligand, RET promotes apoptosis.2
Changes in RET can be associated with a gain or a loss of function. Loss-of-function mutations in RET can result in intestinal aganglionosis, known as Hirschsprung disease, and congenital anomalies of the kidney and urinary tract.2 Gain-of-function changes, including mutations and fusions, have been associated with malignancies. Chromosomal rearrangements involving RET generate fusion transcripts that pair the 3′ end of RET with the 5′ end of another gene.4 These fusions can result in ligand-independent activation of RET,4 and because in all fusions the tyrosine kinase function of RET is preserved,5 this results in unchecked cellular proliferation.
While many papillary thyroid cancer (PTC) cases are associated with BRAF, RAS, or NTRK1 mutations, those that are negative may contain chromosomal rearrangements that disrupt RET.2 At this time, 13 oncogenic RET/PTC fusions have been identified,6 and approximately 90% of RET rearrangements are RET/PTC1 and RET/PTC3.2 The frequency of RET mutations or fusions varies widely but has been identified in 5% to 40% of cases of PTC.5 RET/PTC fusions are also more common among younger patients (67% of patients aged 4-19 years) versus older patients (32% of patients aged 31-80 years).6 Ionizing radiation is also highly associated with RET/PTC fusions expression; among individuals living near Chernobyl who were exposed to radiation, approximately 72% of tumors contained RET/PTC fusions.6 RET/PTC expression leads to thyroid cell transformation, and the rearrangements may occur frequently in benign thyroid diseases; thus, it is likely that additional oncogenic drivers play a role in preventing apoptosis and allowing cellular proliferation that results in PTC.2
RET gain-of-function point mutations may also be present in 50% to 65% of sporadic medullary thyroid cancer (MTC) cases.4,5 While rare germline RET mutations have been found in cases of MTC with unclear pathogenic effects, somatic RET mutations are associated with an aggressive MTC phenotype.2 Germline RET missense mutations are found in nearly all multiple endocrine neoplasia type 2 syndromes, which confer increased risk for MTC, and are involved in the pathogenesis of approximately 25% of MTCs.2,4
Given its prevalence in thyroid cancers, RET has become a promising target for treatment. Several agents have demonstrated in vitro RET kinase inhibition that has been associated with confirmed response and durable disease control.4
- O’Leary C, Xu W, Pavlakis N, et al. Rearranged during transfection fusions in non-small cell lung cancer. Cancers (Basel). 2019;11:620.
- Santoro M, Carlomagno F. Central role of RET in thyroid cancer. Cold Spring Harb Perspect Biol. 2013;5:a009233.
- Carlomagno F. Thyroid cancer: role of RET and beyond. Eur Thyroid J. 2012;1:15-23.
- Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15:151-167.
- Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18:865-875.
- Prescott JD, Zeiger, MA. The RET oncogene in papillary thyroid carcinoma. Cancer. 2015;121:2137-2146.