Targeted therapy and drug resistance in thyroid cancer

Thyroid cancer is the most common endocrine malignancy, the incidence of which has increased significantly over the past decades. Advanced thyroid cancers, especially locally advanced or metastatic poorly differentiated thyroid cancer and anaplastic thyroid cancer, also show increased incidence and mortality rate. The treatment of advanced thyroid cancer has undergone rapid evolution in the last decade, with multiple kinase inhibitor drug approvals for each subtype of thyroid cancer. However, the drug efficacy in those patients is not satisfying owing to primary and secondary drug resistance. Hence, a full comprehension of the underlying mechanisms is worth discussing. In this review, we introduce the clinical application of existing kinase inhibitors that are recommended for patients with advanced thyroid cancer and discuss several significant resistance mechanisms, including key signaling pathway regulation, the tumor microenvironment, ABC transporters, epithelial-to-mesenchymal transition and cancer stem-like cells, apoptosis, autophagy, and aerobic glycolysis. Understanding the molecular basis of drug resistance in thyroid cancer will be helpful for the enhancement of drug combination therapy and promoting the development of new drugs against advanced thyroid cancer.