The importance of the RET gene in thyroid cancer and therapeutic implications

Abstract

Since the discovery of the RET receptor tyrosine kinase in 1985, alterations of this protein have been found in diverse thyroid cancer subtypes. RET gene rearrangements are observed in papillary thyroid carcinoma, which result in RET fusion products. By contrast, single amino acid substitutions and small insertions and/or deletions are typical of hereditary and sporadic medullary thyroid carcinoma. RET rearrangements and mutations of extracellular cysteines facilitate dimerization and kinase activation, whereas mutations in the RET kinase coding domain drive dimerization-independent kinase activation. Thus, RET kinase inhibition is an attractive therapeutic target in patients with RET alterations. This approach was initially achieved using multikinase inhibitors, which affect multiple deregulated pathways that include RET kinase. In clinical practice, use of multikinase inhibitors in patients with advanced thyroid cancer resulted in therapeutic efficacy, which was associated with frequent and sometimes severe adverse effects. However, remarkable progress has been achieved with the identification of novel potent and selective RET kinase inhibitors for the treatment of advanced thyroid cancer. Although expanded clinical validation in future trials is needed, the sustained antitumoural activity and the improved safety profile of these novel compounds is opening a new exciting era in precision oncology for RET-driven cancers. Alterations of RET kinase have been found in diverse thyroid cancer subtypes. This Review describes the RET mutations and gene fusions that can occur in thyroid cancer and highlights specific RET kinase inhibitors that are in clinical and preclinical use. Alterations in RET are frequent key events in thyroid tumorigenesis. Single amino acid mutations and small deletions and/or insertions, or gene fusions involving RET represent oncogenic driving forces in medullary thyroid carcinoma and papillary thyroid carcinoma, respectively. Multitargeted tyrosine kinase inhibitors (TKIs) currently represent the mainstay of treatment for advanced radioiodine-refractory thyroid cancer and advanced medullary thyroid carcinoma. Novel RET TKIs that target RET kinase potently with increased selectivity might be effective and better tolerated than the drugs already in clinical practice for the treatment of advanced thyroid cancer. Alterations in RET are frequent key events in thyroid tumorigenesis. Single amino acid mutations and small deletions and/or insertions, or gene fusions involving RET represent oncogenic driving forces in medullary thyroid carcinoma and papillary thyroid carcinoma, respectively. Multitargeted tyrosine kinase inhibitors (TKIs) currently represent the mainstay of treatment for advanced radioiodine-refractory thyroid cancer and advanced medullary thyroid carcinoma. Novel RET TKIs that target RET kinase potently with increased selectivity might be effective and better tolerated than the drugs already in clinical practice for the treatment of advanced thyroid cancer.