Molecular basis and targeted therapy in thyroid cancer: Progress and opportunities

Thyroid cancer (TC) is the most common endocrine malignancy. Standard treatments for TC include surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy. However, managing anaplastic thyroid cancer (ATC) and RAI-refractory differentiated thyroid cancer (RR-DTC) remains challenging due to issues with recurrence and metastasis. Recently, multi-tyrosine kinase inhibitors (MKIs) and immune checkpoint inhibitors combined with MKIs have emerged as novel therapeutic strategies for controlling the progression of differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC), and ATC.

This review explores the molecular underpinnings of TC, summarizes current and emerging molecularly targeted therapies, and identifies potential new therapeutic targets. We examine approved tyrosine kinase inhibitors for systemic therapy, including lenvatinib, sorafenib, and cabozantinib for DTC; vandetanib, cabozantinib, and RET-specific inhibitors (selpercatinib and pralsetinib) for MTC; and the combination of dabrafenib and trametinib for ATC. Additionally, we discuss promising treatments currently in clinical trials that may soon be incorporated into practice, and briefly address resistance mechanisms to targeted therapies, highlighting the importance of BLU-667 personalized medicine in developing effective second-line treatments.