Targeted therapies in advanced differentiated thyroid cancer

•Sorafenib and lenvatinib are approved for advanced differentiated thyroid cancer.•MAPK and PI3K/AKT/mTOR pathways play a central role in differentiated thyroid cancer.•Combination of BRAF and MEK inhibitors is being investigated in thyroid cancer.•The TCGA characterized papillary thyroid cancer into BRAF- and RAS-driven tumors.•Redifferentiation agents have an important potential for thyroid cancer treatment.

Differentiated thyroid cancer is the most common endocrine malignancy, and its incidence has been rising rapidly over the past 10 years. Although most patients with this disease have an excellent prognosis, a subset develops a more aggressive disease phenotype refractory to conventional therapies. Until recently, there was no effective therapy for these patients. With increasing knowledge of the molecular pathogenesis of thyroid cancer, novel targeted therapies are being developed for this group of patients. Sorafenib and lenvatinib, small-molecule multikinase inhibitors, were approved for the treatment of progressive, symptomatic, radioactive iodine refractory, advanced differentiated thyroid cancer in 2013 and 2015, respectively. This represents a major innovation in the therapy of patients with advanced thyroid cancer. However, these therapies still have many limitations and further research needs to be pursued with the ultimate goal of providing safe and effective personalized therapy for patients with advanced thyroid cancer.