RET

Official Full Name

ret proto-oncogene

Organism

Homo sapiens

GeneID

5979

Background

This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

Synonyms

PTC; MTC1; HSCR1; MEN2A; MEN2B; CDHF12; CDHR16; RET-ELE1;

Bio Chemical Class

Kinase

Protein Sequence

MAKATSGAAGLRLLLLLLLPLLGKVALGLYFSRDAYWEKLYVDQAAGTPLLYVHALRDAPEEVPSFRLGQHLYGTYRTRLHENNWICIQEDTGLLYLNRSLDHSSWEKLSVRNRGFPLLTVYLKVFLSPTSLREGECQWPGCARVYFSFFNTSFPACSSLKPRELCFPETRPSFRIRENRPPGTFHQFRLLPVQFLCPNISVAYRLLEGEGLPFRCAPDSLEVSTRWALDREQREKYELVAVCTVHAGAREEVVMVPFPVTVYDEDDSAPTFPAGVDTASAVVEFKRKEDTVVATLRVFDADVVPASGELVRRYTSTLLPGDTWAQQTFRVEHWPNETSVQANGSFVRATVHDYRLVLNRNLSISENRTMQLAVLVNDSDFQGPGAGVLLLHFNVSVLPVSLHLPSTYSLSVSRRARRFAQIGKVCVENCQAFSGINVQYKLHSSGANCSTLGVVTSAEDTSGILFVNDTKALRRPKCAELHYMVVATDQQTSRQAQAQLLVTVEGSYVAEEAGCPLSCAVSKRRLECEECGGLGSPTGRCEWRQGDGKGITRNFSTCSPSTKTCPDGHCDVVETQDINICPQDCLRGSIVGGHEPGEPRGIKAGYGTCNCFPEEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSAFCIHCYHKFAHKPPISSAEMTFRRPAQAFPVSYSSSGARRPSLDSMENQVSVDAFKILEDPKWEFPRKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLKQVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDHPDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVYEEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERLFNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAASTPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRADGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS

Open

Approved Drug

6 +

Clinical Trial Drug

7 +

Discontinued Drug

1 +

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Detailed Information

The RET (Rearranged during Transfection) gene is located on the long arm of human chromosome 10 (10q11.2), spanning approximately 60 kb and containing 21 exons. It encodes a receptor tyrosine kinase (RTK) whose protein structure consists of an extracellular region—including cadherin-like repeats and a cysteine-rich domain—a transmembrane segment, and an intracellular tyrosine kinase domain. RET has three alternatively spliced isoforms: RET51 (long, 51 amino acids), RET43 (medium, 43 amino acids), and RET9 (short, 9 amino acids), with RET51 and RET9 being predominant. RET51 demonstrates higher efficiency in promoting cellular proliferation and migration. RET activation depends on the binding of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) to the co-receptor GFRα: GFLs such as GDNF or neurturin (NRTN) first form a complex with GFRα1-4, which then induces RET dimerization and intracellular tyrosine phosphorylation, triggering downstream signaling cascades.

Physiological Functions and Molecular Mechanisms

During embryonic development, RET plays critical roles in the nervous system by regulating neural crest cell migration, enteric nervous system formation, and dorsal root ganglion differentiation. RET knockout mice exhibit renal agenesis and die within 24 hours after birth due to congenital megacolon. RET also contributes to organogenesis, including the development of kidneys, thyroid parafollicular cells (C cells), and spermatogenesis. In adults, RET expression is restricted to neuroendocrine tissues such as the adrenal medulla and parathyroid glands, where its role in tissue homeostasis is limited. Once activated, RET signals through multiple pathways: pro-survival and proliferation pathways, including RAS/MAPK and PI3K/AKT, and migration and differentiation pathways such as JAK/STAT and PKC.

Pathological Mechanisms and Disease Associations

Germline RET mutations underlie multiple endocrine neoplasia type 2 (MEN2) syndromes, divided into MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). MEN2A (60-90% of cases) involves mutations in the extracellular cysteine-rich domain (exons 10-11, e.g., C634R), disrupting disulfide bonding and generating ligand-independent homodimers, leading to constitutive downstream signaling and clinical features including medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. MEN2B (5% of cases) typically carries kinase domain mutations such as M918T, enhancing ATP-binding affinity and driving constitutive activation without dimerization; patients present with aggressive MTC, mucosal neuromas, and Marfanoid habitus. FMTC involves mutations in non-cysteine extracellular or kinase domain residues (e.g., G533C, V804M) with slower tumor progression.

In sporadic tumors, RET contributes to papillary thyroid carcinoma (PTC) through chromosomal rearrangements forming RET/PTC fusions, which occur in 10-20% of PTC cases. Breakpoints frequently arise in intron 11, with partner genes such as CCDC6 (RET/PTC1) or NCOA4 (RET/PTC3) providing coiled-coil domains that promote RET dimerization. Ionizing radiation is a major risk factor, with incidence as high as 50-80% among Chernobyl-exposed individuals. RET fusions are also observed in 1-2% of non-small cell lung cancer (NSCLC), such as KIF5B-RET, driving malignancy via MAPK/PI3K pathway activation.

Developmental RET loss-of-function mutations cause Hirschsprung disease, a congenital megacolon due to the absence of enteric ganglion cells, resulting in intestinal obstruction.

Figure 1. Mechanisms of RET activation in cancers. (Drilon A, et al., 2018)

Clinical Applications and Translational Research

Germline RET mutation screening is critical for MEN2 family members to guide prophylactic thyroidectomy, with high-risk mutations such as M918T requiring surgery before one year of age. RET fusions serve as PTC-specific diagnostic biomarkers, with a 60% malignancy prediction value in Bethesda III nodules and mutual exclusivity with BRAF mutations.

Highly selective RET inhibitors have improved outcomes in advanced tumors. Selpercatinib (LOXO-292) is effective against RET fusion-positive NSCLC/thyroid cancers and RET-mutant MTC, achieving objective response rates (ORR) of 64-79%. Pralsetinib (BLU-667) targets gatekeeper RET mutations V804M/L, with an ORR of 60% in MTC patients. Resistance mechanisms include secondary mutations such as RET G810R/S or bypass pathway activation like MET amplification, with next-generation inhibitors such as TPX-0046 currently in clinical trials.

Challenges and Future Directions

RET-targeted therapy faces challenges, including tissue-specific toxicities, as inhibitors may block physiological RET signaling, causing hypertension and delayed wound healing. Tumor heterogeneity is another concern, as sporadic MTC often exhibits mutual exclusivity between RET M918T and HRAS/KRAS mutations, necessitating combination approaches. Resistance management requires dual-target inhibitors (e.g., RET/MET) or combination with immunotherapy (e.g., PD-1 inhibitors). Future research focuses on RET’s role in the tumor immune microenvironment, antibody-drug conjugate (ADC) therapies for low RET-expressing tumors, and patient-derived organoid (PDO)-based drug sensitivity platforms. As a dual regulator of organ development and oncogenesis, RET remains a key target in precision oncology, with ongoing studies addressing resistance mechanisms and combinatorial strategies.

Reference

Li AY, McCusker MG, Russo A, et al. RET fusions in solid tumors. Cancer Treat Rev. 2019 Dec;81:101911.
Drilon A, Hu ZI, Lai GGY, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018 Mar;15(3):151-167.

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