The RET (REarranged during Transfection) kinase is a protein that plays a central role in communication within cells. It functions as a receptor tyrosine kinase, a type of protein embedded in the cell membrane that receives signals from outside the cell and transmits them inward. This signaling cascade influences various cellular activities, including growth, survival, and differentiation. When the RET kinase malfunctions, it can contribute to the development of different health conditions.
Normal Cellular Role
RET functions as a receptor tyrosine kinase, possessing an extracellular domain for signal binding, a transmembrane domain that crosses the cell membrane, and an intracellular domain with enzyme activity. This enzyme activity adds phosphate groups to specific tyrosine amino acids on other proteins, acting like a molecular switch to activate downstream cellular processes.
To become active, RET binds to specific signaling molecules called glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs). These GFLs form a complex with co-receptors, bringing two RET molecules together. This clustering activates RET molecules through autophosphorylation, initiating a cascade of internal signals. The activated RET protein then serves as a docking site for adaptor proteins, relaying the signal into the cell.
These signaling pathways regulate fundamental cellular behaviors like cell proliferation, migration, and survival. Such processes are integral to the proper formation and maintenance of several organ systems throughout the body.
RET signaling is important for the development and function of the nervous system. It guides the formation of nerve cells in both the peripheral and central nervous systems, including the enteric nervous system that controls gut function.
Beyond the nervous system, RET also plays a part in kidney development. It is involved in the formation of the ureteric bud and its branching, essential for proper kidney structure and function.
RET is also found in certain endocrine cells, contributing to their normal development and physiological roles. Its presence in diverse tissues highlights its broad involvement in orchestrating complex biological processes. Precise regulation of RET activity is fundamental for healthy cellular function and organ development.
RET in Cancer Development
Genetic alterations can cause RET kinase to become overactive, leading to uncontrolled cell growth and division, a hallmark of cancer. These alterations involve changes in the RET gene, primarily through point mutations or gene fusions.
Point mutations are single “misspellings” in the RET gene’s DNA sequence, making the resulting RET protein constantly active. Gene fusions occur when the RET gene abnormally joins another gene, creating a hybrid protein that is continuously “on.”
When RET is aberrantly activated, it functions as an oncogene, meaning it drives the formation and progression of cancer. The perpetually active RET protein sends persistent growth signals within the cell, overriding normal regulatory mechanisms. This continuous signaling promotes rapid, uncontrolled cell multiplication, contributing to tumor development.
RET alterations are found in several cancer types. Medullary thyroid cancer (MTC) is frequently associated with RET alterations, where activating point mutations are a common cause. These mutations can be inherited or arise sporadically, affecting nearly all hereditary MTC cases and a substantial portion of sporadic cases.
Papillary thyroid cancer (PTC) is linked to RET gene fusions. These fusions involve the RET gene joining other partner genes, leading to an activated RET protein in about 10-20% of PTC cases.
RET fusions are also found in a subset of non-small cell lung cancer (NSCLC), accounting for approximately 1-2% of cases. These cases are often observed in younger patients with little to no smoking history. Specific fusion partners vary, with KIF5B and CCDC6 being common examples. Understanding these genetic changes in RET is important for identifying patients who may benefit from targeted therapies.
RET in Developmental Disorders
In contrast to its role in cancer, genetic alterations in the RET gene can lead to developmental problems due to reduced or lost function. These are typically “loss-of-function” mutations, which prevent the RET protein from being produced correctly or functioning effectively.
Insufficient RET signaling disrupts normal developmental processes that depend on its activity. A primary example is Hirschsprung’s disease, a congenital condition characterized by the absence of specialized nerve cells, called enteric neurons, in segments of the large intestine. These nerves are essential for coordinated muscle contractions that move waste through the digestive tract. Without them, individuals experience severe constipation and intestinal blockage.
RET signaling is essential for the migration, proliferation, and differentiation of neural crest cells that form the enteric nervous system during embryonic development. Mutations that inactivate RET can impair these processes, resulting in incomplete formation of the nerve network in the bowel.
More than 200 different RET gene mutations have been identified as causes of Hirschsprung’s disease, affecting various parts of the protein and impacting its ability to transmit signals. These mutations significantly decrease RET activity, contrasting with the overactive RET seen in cancer. This distinction highlights how different genetic changes in the same gene can lead to vastly different health outcomes, either by overactivating or hindering cellular processes.
Targeting RET in Medicine
Understanding RET kinase’s role in disease has led to the development of targeted therapies, which represent a precise approach to treatment. Unlike traditional treatments like chemotherapy, which affect many cell types, targeted therapies are designed to specifically interfere with abnormal protein activity that drives disease. This specificity can lead to more effective treatments with fewer side effects.
For cancers driven by overactive RET, drugs known as RET inhibitors have been developed. These inhibitors block the abnormal enzymatic activity of RET kinase, interrupting continuous growth signals that fuel cancer cells. By selectively targeting the deregulated RET protein, these medications aim to halt tumor growth and progression.
RET inhibitors are part of personalized medicine, where treatments are tailored to a patient’s specific genetic alterations. Before initiating therapy, patients undergo genetic testing, often through next-generation sequencing of tumor tissue or liquid biopsies, to identify if their cancer harbors RET mutations or fusions. This diagnostic step ensures the treatment is appropriate for the individual’s cancer.
Two selective RET inhibitors, selpercatinib and pralsetinib, have received regulatory approvals for treating RET fusion-positive non-small cell lung cancer, RET fusion-positive thyroid cancers, and RET mutation-positive medullary thyroid cancer. These highly selective inhibitors offer improved efficacy and reduced off-target side effects compared to older multi-kinase inhibitors. The development of these therapies has changed the treatment landscape for patients with RET-driven cancers, offering more precise and effective options.