The RET gene encodes a receptor on the cell surface that helps tissues grow, survive, and organize during development, and mutations in this single gene sit at the center of an unusually wide range of human diseases. When RET loses function, the result can be missing nerve cells in the gut or kidneys that never fully form. When RET gains function through activating mutations or chromosomal rearrangements, the result can be cancer, most famously medullary thyroid carcinoma but also lung cancer, and potentially tumors in a half-dozen other organs. That dual personality makes RET one of the more fascinating genes in modern oncology and a growing target for precision medicine.
What RET Does in a Healthy Body
RET stands for “rearranged during transfection,” a name inherited from the laboratory technique that first identified it. The protein it produces is a receptor tyrosine kinase, meaning it sits in the cell membrane, receives a chemical signal from outside the cell, and relays that signal inward to trigger specific cellular responses. Under normal conditions, a growth factor called GDNF (glial cell line-derived neurotrophic factor) binds to a helper receptor on the cell surface, and that complex then activates RET, causing two RET molecules to pair up and switch on internal signaling cascades that promote cell survival and growth.1PubMed Central. A network map of GDNF/RET signaling pathway in physiological and pathological conditions2PubMed. Intracellular RET signaling pathways activated by GDNF
During embryonic development, RET is active in the tissues that will become the kidneys, the enteric nervous system (the network of nerves running the length of the gut), and several types of nerve clusters including those that later form the autonomic nervous system.3JMA Journal. Roles of the RET Proto-oncogene in Cancer and Development This explains why problems with RET tend to show up as developmental defects in very specific organs rather than as widespread dysfunction.
When RET Fails During Development
Loss-of-function mutations in RET are perhaps best known for causing Hirschsprung disease, a condition in which nerve cells fail to colonize part of the large intestine. Without those nerves, the affected segment of bowel cannot push food along, leading to severe constipation or intestinal obstruction in newborns. Animal studies have shown that even a single copy of a defective RET gene can produce this effect: in one mouse model, all newborn animals carrying the mutation had some degree of missing or reduced gut nerves, with half showing complete absence of nerve cells in portions of the colon.4PubMed Central. A Single RET Mutation in Hirschsprung Disease Induces Intestinal Aganglionosis Via a Dominant-Negative Mechanism Another mouse model carrying a different RET mutation recapitulated features of Hirschsprung disease in heterozygous animals while also causing severe kidney defects and death around birth in homozygous animals.5PubMed Central. The Ret(C620R) mutation affects renal and enteric development in a mouse model of Hirschsprung’s disease
The kidney connection is clinically significant. RET mutations have been identified in a spectrum of congenital kidney and urinary tract anomalies, sometimes occurring alongside Hirschsprung disease and sometimes in isolation.6PubMed Central. The many faces of RET dysfunction in kidney In one study of fetuses with bilateral renal agenesis (both kidneys completely absent), about a third carried RET mutations, and roughly a fifth of those with unilateral agenesis did too.7PubMed Central. Renal aplasia in humans is associated with RET mutations Across the broader category of congenital kidney and urinary tract anomalies, RET mutations are found in roughly 5 to 30 percent of patients, depending on the specific condition and the population studied.8PubMed Central. To bud or not to bud: the RET perspective in CAKUT
Gain-of-Function Mutations and Hereditary Cancer
The same gene that causes developmental disease when it is too quiet can drive cancer when it is too active. Point mutations that switch RET on permanently, without needing a GDNF signal, are the hallmark of a group of inherited cancer syndromes collectively called multiple endocrine neoplasia type 2 (MEN2). These syndromes include MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC), each associated with different specific RET mutations and carrying different levels of risk.9PubMed. Molecular biology of the MEN2 gene
The discovery that specific RET mutations predicted the type and aggressiveness of MEN2 was a landmark in cancer genetics, because it enabled direct genetic testing for at-risk family members. Today, people identified as carriers of germline RET mutations undergo risk assessment and can be offered preventive surgery tailored to the particular mutation they carry.10PubMed. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma RET mutations also serve double duty as prognostic markers: genetic screening can help clinicians classify patients into risk categories and shape the course of surveillance and treatment.11PubMed Central. Genetic alterations in medullary thyroid cancer: diagnostic and prognostic markers
RET in Thyroid Cancer
Medullary thyroid carcinoma (MTC) is the cancer most tightly linked to RET. In the hereditary forms described above, germline mutations are the driver. In sporadic (non-inherited) MTC, somatic RET mutations acquired during a person’s lifetime play a comparable role, and patients whose tumors carry these mutations, especially the M918T mutation, tend to present at a more advanced stage and have worse outcomes than those with RAS-driven tumors.12iScience. Genetic Landscape of Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing
RET also shows up in papillary thyroid carcinoma (PTC), the most common type of thyroid cancer, but through a different mechanism. Instead of point mutations, chromosomal rearrangements fuse part of the RET gene to another gene, creating a hybrid protein that is constitutively active. These RET fusion proteins were among the first oncogenic events ever identified in PTC and are estimated to play a role in roughly a fifth of cases.13PubMed. The RET oncogene in papillary thyroid carcinoma RET fusions in PTC are about three times more common in children and adolescents than in adults.14PubMed Central. RET fusion genes in pediatric and adult thyroid carcinomas: cohort characteristics and prognosis
RET Fusions Beyond the Thyroid
RET fusions are not exclusive to the thyroid. In non-small cell lung cancer (NSCLC), RET fusions occur in roughly 1 to 2 percent of cases, making them uncommon but clinically actionable. The most frequent fusion partners are KIF5B and CCDC6, which together account for about 90 percent of lung cancer RET fusions.15PubMed Central. Characterization of RET fusions via integrated DNA and RNA sequencing in early-stage non-small cell lung cancer In a large Chinese multicancer analysis, RET fusions were also detected in colorectal, pancreatic, and breast cancers at lower rates, with different cancers tending to favor different fusion partners.16PubMed Central. Identification of RET fusions in a Chinese multicancer retrospective analysis by next-generation sequencing
Beyond fusions, changes in RET expression (the gene being overproduced rather than structurally altered) have been reported in a wide range of solid tumors, including a substantial fraction of invasive breast cancers and pancreatic ductal adenocarcinomas, as well as colorectal cancer, melanoma, small cell lung cancer, and neuroblastoma.17Cancer Treatment Reviews. The RET Gene: Role in Cancer, Disease, and Treatment The clinical significance of RET overexpression versus outright structural alterations is still being sorted out, but it underscores just how many cancer types this gene touches.
How RET Alterations Are Detected
Finding a RET alteration in a tumor matters, because it can open the door to targeted therapy. Several testing methods exist, and they do not all perform equally. DNA-based next-generation sequencing (NGS) on tissue biopsies has shown very high sensitivity and specificity for RET fusions.18Clinical Cancer Research. A Performance Comparison of Commonly Used Assays to Detect RET Fusions Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are older techniques that can detect many fusions but show lower sensitivity for certain fusion partners, meaning they may miss some cases.
Liquid biopsy, which detects circulating tumor DNA shed into the bloodstream, is increasingly used as a less invasive alternative to tissue biopsy. A round-robin comparison of three commercial liquid biopsy platforms found that each detected RET rearrangements in roughly 60 to 70 percent of known positive cases, a sensitivity that rose somewhat when lab analysts manually reviewed borderline results.19Clinical Cancer Research. Round-Robin Comparison of RET Rearrangement Detection in ctDNA That gap between liquid and tissue biopsy narrows when the amount of tumor DNA in the blood is higher, but it means a negative liquid biopsy result does not rule out a RET fusion entirely.20Clinical Cancer Research. Circulating Tumor DNA Enables Sensitive Detection of Actionable Gene Fusions and Rearrangements Across Cancer Types
Targeted RET Inhibitors
The treatment landscape for RET-driven cancers has shifted considerably. Earlier drugs approved for RET-related thyroid cancers, such as cabozantinib, vandetanib, lenvatinib, and sorafenib, are all multikinase inhibitors. They hit RET among many other targets, which means they work but come with broader side-effect profiles because they are not designed to be RET-specific.21PubMed. Role of RET protein-tyrosine kinase inhibitors in the treatment RET-driven thyroid and lung cancers
The real breakthrough came with selpercatinib and pralsetinib, selective RET inhibitors designed to bind RET far more tightly than other kinases. Both have been approved by the FDA for RET-altered thyroid and lung cancers and have shown strong response rates. However, these drugs are not permanent solutions for everyone. When patients progress on a selective RET inhibitor and then try a different first-generation RET inhibitor, response rates and progression-free survival are modest. In a registry study, rechallenge with a different RET inhibitor after progression yielded response rates around 18 to 20 percent and a median time before further progression of only two to four months. The picture was brighter for patients who had originally stopped a RET inhibitor because of side effects rather than disease progression: switching to a different selective inhibitor produced a response rate of about 57 percent and a median progression-free interval near ten months, though about a third experienced serious recurrent side effects.22Journal of Clinical Oncology. Rechallenge with first-generation RET inhibitors in RET-rearranged NSCLC pre-treated with selpercatinib or pralsetinib
Why Tumors Stop Responding and What Comes Next
Resistance to selective RET inhibitors falls into two broad categories. On-target resistance involves new mutations within the RET gene itself that change the shape of the drug-binding pocket. The most commonly reported are solvent-front mutations like G810C, G810S, and G810R, which create a physical clash between the drug molecule and the mutated protein. Gatekeeper mutations at position V804 are another example.23Nature Communications. The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers Bypass resistance, on the other hand, leaves RET unchanged but activates alternative signaling pathways. MET amplification is one well-characterized bypass mechanism, accounting for roughly 5 percent of resistance cases, and laboratory work has shown it can shift the amount of drug needed to kill cancer cells by more than a hundred-fold.24Clinical Cancer Research. Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion–Positive Lung Cancer by Combining Selpercatinib with Crizotinib25PubMed Central. Selpercatinib and capmatinib combination promotes sustained complete response in novel ISOC1-RET fusion lung cancer after resistance to RET inhibitor via MET amplification Activation of the MAPK signaling pathway is another common bypass route.26PubMed Central. Mechanisms of resistance to RET-directed therapies
One promising experimental approach to overcoming on-target resistance is PROTAC technology. Instead of simply blocking the RET protein, PROTACs are designed to tag it for destruction by the cell’s own protein-disposal machinery. Early-stage compounds have shown the ability to degrade RET proteins carrying solvent-front mutations that make current drugs ineffective, and they have demonstrated antitumor activity in mouse models of resistant disease.27Journal of Medicinal Chemistry. Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer Cells Harboring RET Solvent-Front Mutations Another PROTAC compound, RD-23, showed strong activity against cells harboring various RET mutations, was orally bioavailable in animal studies, and outperformed selpercatinib in a mouse model of G810C-resistant cancer.28PubMed. Discovery of a Selective and Orally Bioavailable RET Degrader with Effectiveness in Various Mutations These are still preclinical results, but they represent a conceptually different way of tackling resistance that researchers are actively pursuing.
Preventive Surgery for RET Mutation Carriers
For families carrying germline RET mutations that cause MEN2, the question is not whether medullary thyroid carcinoma will develop but when. Current guidelines from the American Thyroid Association stratify RET mutations into risk categories. The highest-risk mutations call for thyroid removal within the first year of life. High-risk mutations generally warrant surgery by age five, or sooner if calcitonin levels start climbing. For moderate-risk mutations, timing is more flexible and involves shared decision-making between families and clinicians, weighing the cancer risk against the surgical risks in young children.29International Journal of Pediatric Otorhinolaryngology. Outcomes of pediatric prophylactic thyroidectomy in MEN2: A systematic review
Long-term data suggest that prophylactic thyroidectomy is safe and effective, achieving cure even in adults who were not identified as carriers until later in life. Still, recurrences have been documented at long follow-up when microscopic cancer was already present at the time of surgery, reinforcing the rationale for operating early in childhood before any tumor has a chance to form.30PubMed Central. Prophylactic and Early Thyroidectomy in RET Germline Mutation Carriers in Pediatric and Adult Population: Long-Term Outcomes of a Series of 63 Patients
RET Mutations and the Response to Immunotherapy
An unexpected finding has emerged from large-scale analyses of patients treated with immune checkpoint inhibitors: tumors carrying RET mutations appear to respond better to immunotherapy than those without. In a study of nearly 3,000 patients receiving immune checkpoint inhibitors across 11 tumor types, RET-mutant tumors were associated with significantly better overall survival and higher response rates compared to RET-wildtype tumors.31PubMed Central. Mutation of rearranged during transfection (RET) is associated with enhanced tumor immunogenicity and favorable outcomes in pan-cancer immunotherapy Multi-omics analysis has suggested that RET-mutant tumors tend to have higher immune cell infiltration, increased expression of immune checkpoints, and enhanced immunogenicity overall, potentially explaining why the immune system responds more vigorously when unleashed by checkpoint drugs.32PubMed. Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts
This is still an evolving area. In small cohorts of lung cancer patients with RET rearrangements treated with immunotherapy, disease control rates have been encouraging.33Cancer Treatment and Research Communications. Pathological characteristics and tumour immune microenvironment of lung malignancies with RET rearrangement Whether immunotherapy should be combined with targeted RET inhibitors, and in what sequence, remains an open question, but the immunological profile of RET-altered tumors makes it a question worth asking.
RET Beyond Cancer: Parkinson’s Disease Research
Because RET is the receptor for GDNF, a growth factor critical for the survival of dopamine-producing neurons, it has attracted attention in the search for treatments for Parkinson’s disease. The logic is straightforward: if you can activate RET in the brain, you might be able to protect the neurons that Parkinson’s disease destroys. Delivering GDNF itself into the brain has been explored for years but is technically difficult because large protein molecules do not cross the blood-brain barrier easily.
Researchers have developed small-molecule compounds called BT compounds that activate RET signaling and can reach the brain after systemic administration. One such compound, BT44, promoted the survival of dopamine neurons in culture, protected them from a toxin used to model Parkinson’s, and reduced motor impairment in rats with chemically induced Parkinson-like damage. The protective effects depended on RET being present: neurons from mice engineered to lack RET did not benefit, confirming that the drug works through the RET pathway.34PubMed Central. Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats Broader research into the GDNF-RET signaling axis continues to support its potential for neuroprotection and neuronal regeneration, with related strategies also being explored for tau-related pathologies.35PubMed. Molecular mechanisms of GDNF/GFRA1/RET and PI3K/AKT/ERK signaling interplay in neuroprotection
An Evolutionarily Ancient Gene
One reason RET mutations have such far-reaching consequences is that the gene is deeply conserved across vertebrate evolution. Comparison of the RET protein across mammals, birds, and fish shows that its key structural features have been maintained over hundreds of millions of years of evolution, suggesting that each part of the protein has a distinct function that natural selection has preserved.36PubMed. Conservation of RET proto-oncogene splicing variants and implications for RET isoform function This conservation extends beyond the protein itself: the regulatory DNA sequences that control where and when RET is expressed appear to maintain their function between humans and zebrafish despite having essentially no detectable similarity at the sequence level.37PubMed. Conservation of RET regulatory function from human to zebrafish without sequence similarity
This evolutionary perspective has practical implications. Researchers have used cross-species alignment of the RET protein to predict whether newly discovered mutations are likely to be harmful or benign. A model combining evolutionary conservation data with the physical and chemical properties of amino acid substitutions proved substantially more accurate at predicting the effect of Hirschsprung-associated mutations than conservation data alone.38PubMed Central. Phenotype-genotype correlation in Hirschsprung disease is illuminated by comparative analysis of the RET protein sequence In other words, learning how evolution has shaped RET helps clinicians interpret new variants when they are found in patients today.
The Affordability Gap
Selective RET inhibitors have been transformative for patients with RET-driven cancers, but they are expensive, and formal cost-effectiveness analyses have raised difficult questions. In one modeling study comparing first-line selpercatinib to chemotherapy for RET fusion-positive advanced NSCLC, selpercatinib produced a small incremental gain in quality-adjusted survival but at a cost that far exceeded standard willingness-to-pay thresholds. The study estimated that the price of selpercatinib would need to drop by roughly 70 percent or more to meet commonly used benchmarks of cost-effectiveness.39SpringerLink / Clin Transl Oncol. First-line versus second-line use of selpercatinib in treatment of RET fusion-positive advanced non-small cell lung cancer: a cost-effectiveness analysis That finding does not mean the drug is not worthwhile for individual patients, but it illustrates a tension that runs through precision oncology: the narrower the target population, the higher the per-patient cost tends to be, and health systems worldwide are still working out how to pay for it.