Endocrinology and metabolism (Seoul, Korea)Oct 1, 2019

Thyroid Cancer That Does Not Respond to Radioactive Iodine and Treatments to Make It Responsive Again

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Mar 28, 2026

Abstract

The functionality of the sodium iodide symporter (NIS) in differentiated thyroid cancer (DTC) cells is crucial for effective post-surgical radioactive iodine (RAI) therapy.

Dedifferentiation of DTC may reduce the expression of functional NIS, potentially lowering the efficacy of RAI therapy.
Genetic alterations, particularly the RET/papillary thyroid cancer rearrangement, are associated with the onset and progression of DTC.
These genetic changes could activate signaling pathways, such as MAPK and PI3K, contributing to dedifferentiation.
Reduced expression of iodide-handling genes in thyroid cancer is linked to resistance to RAI therapy.
Emerging therapies aim to restore iodine uptake by targeting the expression of iodine-metabolizing genes in RAI-refractory DTC patients.

Simplified

The retained functionality of the sodium iodide symporter (NIS) expressed in differentiated thyroid cancer (DTC) cells allows the further utilization of post-surgical radioactive iodine (RAI) therapy, which is an effective treatment for reducing the risk of recurrence, and even the mortality, of DTC. Whereas, the dedifferentiation of DTC could influence the expression of functional NIS, thereby reducing the efficacy of RAI therapy in advanced DTC. Genetic alternations (such asand the rearranged during transfection [RET]/papillary thyroid cancer [PTC] rearrangement) have been widely reported to be prominently responsible for the onset, progression, and dedifferentiation of PTC, mainly through activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling cascades. These genetic alternations have been suggested to associate with the reduced expression of iodide-handling genes in thyroid cancer, especially thegene, disabling iodine uptake and causing resistance to RAI therapy. Recently, novel and promising approaches aiming at various targets have been attempted to restore the expression of these iodine-metabolizing genes and enhance iodine uptake throughstudies and studies of RAI-refractory (RAIR)-DTC patients. In this review, we discuss the regulation of NIS, known mechanisms of dedifferentiation including the MAPK and PI3K pathways, and the current status of redifferentiation therapy for RAIR-DTC patients. BRAF NIS in vitro

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Thyroid Cancer That Does Not Respond to Radioactive Iodine and Treatments to Make It Responsive Again

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