RetEdit
Ret
Ret, commonly written as RET, is a gene encoding a receptor tyrosine kinase that binds glial cell line-derived neurotrophic factor (GDNF) family ligands through GFRalpha co-receptors. It is a proto-oncogene central to the normal development of neural crest–derived structures, particularly the enteric nervous system and the kidneys. Because of its role in cell growth and differentiation, alterations in RET can give rise to developmental disorders or drive malignant transformation in several cancers, making it a focal point of both basic biology and targeted therapy.
From a practical standpoint, RET operates at the crossroads of signal transduction and development. The protein consists of an extracellular ligand-binding region, a single transmembrane domain, and an intracellular kinase domain that becomes activated upon ligand binding and receptor dimerization. Signals propagate through downstream pathways such as the MAPK/ERK and PI3K/AKT cascades, coordinating cell survival, proliferation, and migration. These processes are especially important during the formation of the enteric nervous system, kidney morphogenesis, and other neural crest derivatives, with disruptions linked to a spectrum of human diseases. For broader context, see RET (gene), receptor tyrosine kinase, GDNF, and neural crest.
Structure and function
RET is a single-pass transmembrane protein that belongs to the family of receptor tyrosine kinases. Its extracellular portion contains structural motifs that mediate ligand recognition in concert with co-receptors from the GDNF family, typically through GFRalpha subunits. The intracellular region houses the kinase domain responsible for autophosphorylation and the initiation of signaling networks. Activation of RET triggers downstream signal transduction pathways, most notably the RAS–MAPK pathway and the PI3K–AKT pathway cascades, which regulate cell fate decisions, survival, and movement. The gene is located on chromosome chromosome 10 and is subject to both gain-of-function and loss-of-function alterations that distinctly affect development and disease. See also proto-oncogene and oncogene for broader context.
RET signaling is essential for the development of several organs and tissues. In the enteric nervous system, RET signaling guides the migration, proliferation, and differentiation of neural crest cells that form the gut’s intrinsic nervous system. In the kidney, RET interactions help shape ureteric bud branching and nephron formation. Disruptions in these pathways can lead to congenital disorders as well as increased susceptibility to later disease. See Hirschsprung disease for a key congenital example, and neural crest for the broader developmental framework.
Clinical significance
Mutations and rearrangements of RET have two broad clinical narratives: developmental disorders arising from inadequate signaling, and cancers driven by aberrant RET activity.
Developmental disorders: Loss-of-function mutations in RET can impair neural crest–derived tissue formation, most notably contributing to Hirschsprung disease, a congenital condition affecting intestinal motility. The extent of RET disruption also influences other neural crest–related anomalies, including defects in the enteric nervous system and kidney development. See Hirschsprung disease and neural crest for related discussions.
Oncogenic alterations: RET can be implicated in cancer via activating germline or somatic mutations, or through chromosomal rearrangements that create fusion genes. In hereditary syndromes such as multiple endocrine neoplasia type 2 (MEN2), activating RET mutations drive medullary thyroid carcinoma and pheochromocytoma, with variants like MEN2A and MEN2B highlighting differing clinical spectra. See medullary thyroid carcinoma, pheochromocytoma, and MEN2 for details.
RET fusions also occur in various solid tumors, most prominently in papillary thyroid carcinoma (RET/PTC rearrangements) and in a subset of non-small cell lung cancer cases. These fusions create constitutively active kinases that can be targeted by selective therapies. See RET fusion and papillary thyroid carcinoma, non-small cell lung cancer for context.
Therapeutic developments
Therapies targeting RET have evolved from broad-spectrum kinase inhibitors to selective RET inhibitors, reflecting the push toward precision medicine.
Multikinase inhibitors: Drugs such as vandetanib and cabozantinib inhibit RET along with other kinases. They have shown activity in RET-driven cancers but come with off-target effects due to their broad profiles. See vandetanib and cabozantinib for more.
Selective RET inhibitors: More recent agents, including selpercatinib and pralsetinib, specifically target RET alterations with improved efficacy and tolerability in patients with RET-altered cancers. See selpercatinib and pralsetinib for details.
Clinical and policy considerations: The development and use of RET-targeted therapies sit at the intersection of science, drug development, and health policy. Debates commonly touch on the balance between strong intellectual property rights to spur innovation and broader access to life-saving medicines, including the costs of targeted therapies and the role of government programs in funding research. See drug development, patent and Myriad Genetics for related discussions, as well as genetic testing and healthcare affordability for access considerations.
Controversies around these topics often surface in the broader discourse on how innovation should be rewarded and how patient access should be balanced with market incentives. From a results-oriented perspective, supporters argue that a robust environment for discovery—underpinned by clear intellectual property rights and predictable returns on investment—delivers the rapid development of new, effective RET-targeted treatments. Critics commonly raise concerns about price, reimbursement, and equitable access, advocating for policies that expand affordability and reduce barriers to genetic testing and targeted therapies.
Wider debates about biomedical innovation sometimes invoke broader cultural criticisms labeled by some as “woke” concerns. Proponents of a market-driven approach contend that real-world progress in cancer therapy depends on maintaining incentives for discovery, clinical trials, and scalable manufacturing. Critics of policy directions that de-emphasize intellectual property or rely heavily on centralized funding may view those moves as dampening innovation. In this frame, the practical emphasis is on delivering tangible patient benefits, while recognizing that policy choices will shape the speed and scope of future RET-related advances.