Ret FusionEdit
Ret fusion, or RET fusion, refers to chromosomal rearrangements that join the RET proto-oncogene with one of several partner genes, creating a fusion oncogene that drives abnormal signaling and tumor growth. These fusions are established oncogenic events in multiple cancers, most notably in non-small cell lung cancer non-small cell lung cancer and papillary thyroid carcinoma papillary thyroid carcinoma. The classic fusion partners include KIF5B, CCDC6, and NCOA4, among others, which contribute to constitutive activation of the RET kinase. For the gene itself, see RET proto-oncogene; for the disease contexts, see non-small cell lung cancer and papillary thyroid carcinoma.
Ret fusions generate a constitutively active RET tyrosine kinase that sends pro-survival and proliferative signals through key downstream pathways. The fusion partner frequently provides dimerization domains or aberrant regulatory control, leading to ligand-independent signaling. The resulting oncogenic signaling commonly engages the MAPK/ERK, PI3K/AKT, and JAK/STAT pathways, among others, to promote tumorigenesis. Different fusion partners can influence the biology, tissue distribution, and sensitivity to targeted therapy, but all hinge on the central feature of RET kinase activation. For more on the gene and its signaling roles, see RET proto-oncogene and tyrosine kinase signaling.
Mechanism and Biology
RET encodes a receptor tyrosine kinase that normally participates in development of the nervous system and kidney, as well as in certain neural crest lineages. In RET fusions, the kinase domain is placed under the control of a heterologous partner, producing a chimeric protein that is active without the normal regulatory inputs. The most studied fusions in cancer include KIF5B-RET and CCDC6-RET, with others such as NCOA4-RET identified across tumor types. The presence of dimerization domains in many partners promotes constitutive RET activation, setting off oncogenic signaling cascades. For diagnostic and therapeutic contexts, see FISH and NGS.
The spectrum of cancers with RET fusions extends beyond NSCLC and thyroid cancer to include certain colorectal and salivary gland tumors, among others. The frequency of RET fusions varies by tumor type: they are a relatively rare driver in NSCLC (a minority of cases) but a more prominent driver in papillary thyroid carcinoma. The exact distribution depends on histology and population, and ongoing sequencing efforts continue to refine the landscape. See papillary thyroid carcinoma and non-small cell lung cancer for disease-specific context.
Detection and Diagnosis
Detection of RET fusions relies on comprehensive molecular testing. DNA-based sequencing panels can identify many fusions, but RNA-based sequencing or targeted RNA assays are often more sensitive for certain fusion transcripts. Conventional methods such as FISH can detect RET rearrangements, but false negatives can occur if the breakpoints are unusual or if the assay lacks the relevant fusion partner coverage. High-quality tissue samples and, increasingly, liquid biopsy approaches are used in some settings to identify RET fusions in patients with advanced disease. See next-generation sequencing for the broader testing framework and FISH for historical methods.
Guidelines from expert bodies typically recommend testing for actionable fusions, including RET, in appropriate contexts (for example, in nonsmoking or light-smoking patients with NSCLC, and in certain thyroid cancers). The goal is to identify candidates for targeted therapy with RET inhibitors. See NCCN guidelines for treatment guidance in RET fusion–positive cancers.
Clinical Significance and Treatment
The clinical relevance of RET fusions has been underscored by the development and regulatory approval of selective RET inhibitors. Two agents, pralsetinib and selpercatinib, have demonstrated meaningful activity across RET fusion–positive cancers and have received regulatory approvals in several indications, reflecting a shift toward precision oncology. In practice, patients with RET fusion–positive NSCLC or thyroid cancers may be candidates for these therapies, subject to clinical assessment and regulatory status.
Pralsetinib (brand name Gavreto) and selpercatinib (brand name Retevmo) are examples of targeted RET inhibitors. They have shown substantial tumor responses and durable benefit in clinical trials, with activity observed across multiple RET fusion partners and tumor types. See pralsetinib and selpercatinib for more on the drugs and their clinical data.
Clinical outcomes in RET fusion–positive cancers generally include high objective response rates and meaningful progression-free intervals, often with a manageable safety profile. Common adverse effects can include hypertension, fatigue, diarrhea, dry mouth, and, less commonly, liver enzyme elevations or ocular toxicity; management typically involves supportive care and dose adjustments per guidelines. See drug safety and Retevmo for product-specific information.
Resistance to RET inhibitors can arise through on-target mutations in RET or through activation of alternative signaling pathways (bypass mechanisms). Ongoing research explores combination strategies and next-line therapies to overcome resistance. See drug resistance for a broader discussion of how tumors adapt to targeted therapies.
The availability of RET inhibitors has also raised discussions about testing policies, access to therapy, and the economics of targeted treatments. While testing and treatment can improve outcomes for many patients, debates continue about cost, equitable access, and the optimal sequencing of therapies in complex cancer care. See healthcare policy for related discussions at the policy level.
History and Research
The recognition of RET fusions as oncogenic drivers emerged from work in thyroid cancers in the 1990s and early 2000s, with subsequent discovery of RET fusions in lung cancer and other tumor types. The identification of common fusion partners such as KIF5B-RET and CCDC6-RET helped define the biology and guided targeted therapy development. The translation from molecular discovery to approved therapies represents a broad collaboration among researchers, clinicians, and regulatory agencies, including the evaluation of pralsetinib and selpercatinib in multiple trial cohorts. See cancer pharmacology for related context and precision oncology for a broader framing.