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The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers or RET-mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAFV600E mutations, or ALK or ROS1 rearrangements. To date, no RET-directed targeted therapeutic has received regulatory approval for the treatment of molecularly defined populations of patients with RET-mutant or RET-rearranged solid tumours. In this Review, we discuss how emerging data have informed the debate over whether the limited success of multikinase inhibitors with activity against RET can be attributed to the tractability of RET as a drug target or to the lack, until 2017, of highly specific inhibitors of this oncoprotein in the clinic. We emphasize that novel approaches to targeting RET-dependent tumours are necessary to improve the clinical efficacy of single-agent multikinase inhibition and, thus, hasten approvals of RET-directed targeted therapies.

RET fusion–positive lung cancer accounts for 1 to 2% of non–small-cell lung cancers. Among previously treated patients with RET fusion–positive lung cancer, 64% of those who received selpercatinib, a RET kinase inhibitor, had a response, and among previously untreated patients, 85% had a response. Approximately one third of the patients had adverse events of grade 3 or higher.

Medullary thyroid cancer often develops in patients with somatic or germline mutations in RET . Selpercatinib is a novel RET inhibitor. In a phase 1–2 trial, a response to selpercatinib occurred in 38 of 55 previously treated patients (69%) and in 64 of 88 previously untreated patients (73%). Toxic effects were mainly low grade.

Rearranged during transfection (RET) is the tyrosine kinase receptor that under normal circumstances interacts with ligand at the cell surface and mediates various essential roles in a variety of cellular processes such as proliferation, differentiation, survival, migration, and metabolism. RET plays a pivotal role in the development of both peripheral and central nervous systems. RET is expressed from early stages of embryogenesis and remains expressed throughout all life stages. Mutations either activating or inhibiting RET result in several aggressive diseases, namely cancer and Hirschsprung disease. However, the physiological ligand-dependent activation of RET receptor is important for the survival and maintenance of several neuronal populations, appetite, and weight gain control, thus providing an opportunity for the development of disease-modifying therapeutics against neurodegeneration and obesity. In this review, we describe the structure of RET, its signaling, and its role in both normal conditions as well as in several disorders. We highlight the differences in the signaling and outcomes of constitutive and ligand-induced RET activation. Finally, we review the data on recently developed small molecular weight RET agonists and their potential for the treatment of various diseases.

The objective of this narrative review is to summarize the efficacy and safety of available therapies for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases. Background information is provided on RET rearrangements in NSCLC and the molecular testing options available as well as an overview of clinical guidelines for molecular testing, which recommend broad molecular testing, including for RET rearrangements. The efficacy and safety of potential treatments for RET fusion-positive NSCLC, including multikinase inhibitors, RET-selective inhibitors, pemetrexed-based therapy, and immunotherapies are reviewed from Phase I/II and `real-world’ studies, alongside an overview of primary and secondary resistance mechanisms. The RET-selective inhibitors, selpercatinib and pralsetinib, are preferred first-line therapy options for patients with RET fusion-positive metastatic NSCLC and are recommended as subsequent therapy if RET inhibitors have not been used in the first-line setting. This review summarizes the efficacy and safety of available therapies for RET fusion-positive non–small cell lung cancer, including in patients with central nervous system metastases.

Using high-coverage targeted next-generation sequencing, this report provides a catalog of genetic alterations in colorectal and lung cancers, identifying previously unknown alterations, such as JAK2 mutations and KIF5B-RET fusions, that may represent druggable targets. Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non–small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8–3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.

Selpercatinib, an oral, selective, brain-penetrant RET kinase inhibitor, was compared with multikinase inhibitors in advanced medullary thyroid cancer. At 12 months, progression-free survival was 86.8% and 65.7%, respectively.

The (Rearranged during Transfection) gene encodes a receptor tyrosine kinase. plays a critical role in embryonic development and postnatal physiology. This review provides a comprehensive overview of -associated disorders, focusing on the molecular mechanisms of activation, associated clinical phenotypes and therapeutic implications. In addition, we present an updated mutation database. mutation database is built through the integration and curation of data from two major mutation repositories: the Leiden Open Variation Database (LOVD) and the Cancer Knowledge Base (CKB) as well as information derived from the ClinVar database. To date, 78 pathogenic mutations have been identified, among these, 71 (91.0%) are single nucleotide substitutions (missense variants), 2 (2.6%) are deletions, 1 (1.3%) are indels, 2 (2.6%) are nonsense mutations and 1 (1.3%) mutation affecting the introns. A pronounced clustering was observed in exons 10-11, accounting for ~60% of cases, suggesting a potential mutational hotspot with structural or functional relevance. : Aberrant activation, resulting from activating missense variants, gene fusions, or overexpression, underlies a wide spectrum of human diseases. These include multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC), Hirschsprung disease, and pheochromocytoma. The existence and use of a database classifying variants in the gene plays a fundamental role in molecular diagnostics and personalized medicine.

In this trial of primary treatment for advanced RET fusion–positive NSCLC, median progression-free survival was 24.8 months with selpercatinib and 11.7 months with chemotherapy with or without pembrolizumab.

Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions ( NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers. Fusions of the gene RET have been described in thyroid and lung cancers. Here, the AUs identify RET gene alterations, including known fusions, novel fusions, and rearrangements in breast cancer (BC) that are involved in the tumorigenic process and show the benefit of RET therapy in a recurrent BC patient carrying the NCOA4-RET fusion.