Perspectives on the Treatment of Advanced Thyroid Cancer: Approved Therapies, Resistance Mechanisms, and Future Directions

Abstract

For differentiated thyroid cancer (DTC), systemic therapy with radioactive iodine (RAI) is utilized for radiosensitive disease, while for radioiodine refractory (RAIR) disease, current standard of care is treatment with multikinase tyrosine kinase inhibitors (TKI). For BRAF-mutant DTC or anaplastic thyroid cancer (ATC), treatment with inhibitors targeting BRAF and MEK are important advances. RET-inhibitors for RET-mutated medullary thyroid cancer (MTC) recently have been FDA-approved for metastatic disease. Nevertheless, treatment of thyroid cancer resistant to current systemic therapies remains an important area of need. Resistance mechanisms are being elucidated, and novel therapies including combinations of BRAF and MEK inhibitors with RAI or other targeted therapies or TKIs combined with checkpoint inhibition are current areas of exploration.

Keywords: BRAF mutation V600; anaplastic thyroid cancer; differentiated thyroid cancer; mechanisms of resistance to therapy; medullary thyroid cancer; papillary thyroid cancer; thyroid cancer; tyrosine kinase inhibitor.

Figure 1

Molecular Pathogenesis of Thyroid Cancer. RAS/RAF/MEK and PI3K/AKT/mTOR pathways are key signaling pathways in thyroid cancer pathogenesis. Mutations in RAS (RASm) or BRAF result in constitutive activation of the MAPK pathway, causing downstream activation of the MAPK and PI3K pathways which promotes cell growth and tumorigenesis. Effective agents include multikinase inhibitors (cabozantinib, vandetanib, sorafenib and lenvatinib) which inhibit receptor tyrosine kinases (RTK) at the cell surface, selective RET inhibitors (selpercatinib and pralsetinib) which inhibit mutant RET RTK (RETm), BRAF V600E inhibitors (dabrafenib and trametinib) and the mTOR inhibitor everolimus. These small molecule inhibitors are used clinically for treatment of RAIR TC with the goal of arresting uncontrolled proliferation.