Redifferentiation Therapies in Thyroid Oncology: Molecular and Clinical Aspects

Since the 1940s, 131-I radioiodine therapy (RIT) has been the primary treatment for metastatic differentiated thyroid cancer (DTC). Approximately half of these patients respond favorably to RIT, achieving partial or complete remission or maintaining long-term stable disease, while the other half develop radioiodine-refractory DTC (RAI-R DTC). The main genomic alteration involved in radioiodine resistance is the activated mitogen-activated protein kinase (MAPK) pathway, which results in the loss of sodium iodide symporters (NIS). Therefore, RAI-R DTC requires alternative treatment options such as tyrosine kinase inhibitors. Over the past decade, several studies have investigated pharmacological induction or enhancement of NIS expression through "redifferentiation" therapies, mainly targeting the MAPK pathway. These novel approaches can restore radioiodine sensitivity in previously refractory patients and, therefore, potentially reestablish the efficacy of RIT. This review discusses various redifferentiation strategies, including their molecular mechanisms and clinical implications.