Medullary thyroid cancer: from molecular biology and therapeutic pitfalls to future targeted treatment perspectives

During the last decades, knowledge of the molecular biology in medullary thyroid carcinoma (MTC) and specifically on the role of rearranged during transfection (RET)-activating mutations in tumorigenesis has led to the evolution of novel targeted therapies, mainly tyrosine kinase inhibitors (TKIs). Vandetanib and cabozantinib have been approved for the management of metastatic progressive MTC. Two novel, highly selective RET inhibitors, selpercatinib and pralsetinib, have recently been approved for the treatment of RET-mutant MTCs and RET-fusion differentiated thyroid cancer. The administration of targeted therapies in MTC patients has changed the therapeutic strategies; however, in the majority of cases, there are no real data showing an improvement of prognosis by TKIs in MTC. Drug resistance remains the main reason for treatment failure. Thus, the understanding of the molecular landscape of tumorigenesis and the mechanisms underlying resistance to targeted therapies is of paramount importance for the further development of more efficient therapies for MTC. The present review focuses on the molecular pathways implicated in MTC tumorigenesis, the approved targeted therapies, the tumoral escape mechanisms, as well as the future perspectives for targeted therapy.