Molecular basis and targeted therapies for radioiodine refractory thyroid cancer

Patients diagnosed with radioiodine refractory thyroid cancer (RAIR-TC) are not amenable to novel I-131 therapy due to the reduced expression of sodium iodide symporter (Na+/I- symporter, NIS) and/or the impairment of NIS trafficking to the plasma membrane. RAIR-TC patients have a relatively poor prognosis with a mean life expectancy of 3-5 years, contributing to the majority of TC-associated mortality. Identifying RAIR-TC patients and selecting proper treatment strategies remain challenging for clinicians. In this review, we demonstrate the updated clinical scenarios or the so-called definitions of RAIR-TC suggested by several associations based on I-131 uptake ability and tumor response post-I-131 therapy. We also discuss current knowledge of the molecular alterations involved in membrane-localized NIS loss, which provides a preclinical basis for the development of targeted therapies, in particular, tyrosine kinase inhibitors (TKIs), redifferentiation approaches, and immune checkpoint inhibitors.

Automated summary

Patients diagnosed with radioiodine refractory thyroid cancer (RAIR-TC) cannot undergo novel I-131 therapy due to reduced expression of sodium iodide symporter (NIS) and/or impairment of NIS trafficking. Identifying RAIR-TC patients and selecting proper treatment strategies remain challenging. This review focuses on the clinical scenarios and molecular alterations involved, providing insights for targeted therapies.