RET Alterations in Thyroid Cancer: Molecular Mechanisms, Targeted Therapies, and Emerging Resistance.

Abstract

RET alterations, including RET fusions and RET mutations, have been identified in thyroid cancer. RET fusions are predominantly found in papillary thyroid carcinoma, whereas RET mutations are primarily associated with medullary thyroid carcinoma. Consequently, RET has emerged as an attractive therapeutic target. Previously, multikinase inhibitors, such as vandetanib and cabozantinib, were primarily used for treatment; however, their efficacy was limited due to off-target effects. Recently, selective tyrosine kinase inhibitors, including selpercatinib and pralsetinib, have been introduced, demonstrating improved selectivity and clinical efficacy. Nevertheless, challenges such as gatekeeper and solvent-front mutations have emerged, contributing to acquired drug resistance. To address this issue, next-generation RET inhibitors, including zeteletinib and SYHA1815, are currently under investigation, reflecting an expanding therapeutic landscape. This article provides an overview of the molecular mechanisms of RET alterations in thyroid cancer, targeted therapies, and emerging resistance to targeted treatment.