RET gene mutations and their importance in targeted therapy of medullary thyroid cancer

Medullary thyroid carcinoma (MTC) is a relatively rare malignancy (approximately 2–5% of all thyroid cancers) characterized by an aggressive clinical course. Activating mutations of the RET (REarranged during Transfection) proto-oncogene play a key role in MTC pathogenesis, being present in all hereditary cases and about half of sporadic cases, and these genetic alterations represent critical targets for targeted therapy. This review summarizes current data on the spectrum of RET gene mutations in MTC and evaluates their significance for targeted therapy. The most common RET mutations (such as point mutations p.Met918Thr and p.Cys634Arg) as well as chimeric rearrangements (fusions) of the RET gene are described, and their association with tumor sensitivity to targeted therapies is discussed. Approaches to therapy selection based on the tumor’s molecular profile are considered, including the use of first-generation RET tyrosine kinase inhibitors (multi-kinase agents, e.g., vandetanib and cabozantinib) and highly selective second-generation RET inhibitors (e.g., selpercatinib and pralsetinib). Special attention is given to the role of molecular genetic testing of RET in optimizing MTC treatment. In conclusion, the need for a personalized approach with molecular stratification of MTC patients by RET status is emphasized, and the promise of new targeted agents directed at various RET mutations is highlighted.

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