Reigniting the Flame for Redifferentiation Strategies in Differentiated Thyroid Cancers - Journey of Tyrosine Kinase Inhibitors to Renewed Radioactive-Iodine Avidity

Sep 29, 2026

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Radioactive-iodine refractory (RAI-R) differentiated thyroid cancers represent a high-risk thyroid cancer subset with poor outcomes despite conventional therapy. Using 2025 American Thyroid Association criteria, the text frames RAI-R definition as dynamic, shaped by imaging protocols and heterogeneous therapeutic responses, and modulated by pharmacologic interventions and neoadjuvant approaches to resensitize tumors to radioactive iodine. It links refractoriness to loss of iodide-metabolizing machinery and highlights MAPK/PI3K-AKT drivers, especially BRAF or RAS alterations and RET/NTRK fusions.

LanguageEnglish

CategoryHealthcare

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Reading Time18 min

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Redefining RAI-R Differentiated Thyroid Cancers

ATA Criteria and Clinical Meaning

Imaging Preparation and Heterogeneous Response

Pharmacologic Resensitization and Neoadjuvant Strategies

Molecular Drivers of Radioiodine Refractoriness

MAPK/PI3K-AKT Alterations and Tumor Biology

Editorial Endocrinol Metab 2025;40:869-875 [https://doi.org/10.3803/EnM.2025.2785](https://doi.org/10.3803/EnM.2025.2785)[ ](https://doi.org/10.3803/EnM.2025.2785)[pISSN 2093-596X](pISSN 2093-596X) · eISSN 2093-5978 Reigniting the Flame for Redifferentiation Strategies in Differentiated Thyroid Cancers: Journey of Tyrosine Kinase Inhibitors to Renewed Radioactive-Iodine Avidity Ji Min Oh 1,2, *, Liya Zhu1,2, *, Byeong-Cheol Ahn 1,2,3,4 1Department of Nuclear Medicine, School of Medicine, Kyungpook National University; 2Cardiovascular Research Institute, Kyungpook National University; 3BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Science, School of Medicine, Kyungpook National University; 4Department of Nuclear Medicine, Kyungpook National University Hospital, Daegu, Korea Radioactive-iodine refractory (RAI-R) differentiated thyroid cancers (DTCs) represent a critical subset of thyroid cancers (TCs) due to their poor prognosis, even when managed with conventional treatment strategies. The 2025 American Thyroid Association (ATA) guidelines suggested strong and supplemental criteria for RAI-R DTCs including: (1) absence of 131I uptake on a post-radioactive-iodine (RAI) scan in the setting of known diseases on structural or 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) imaging; (2) disease progression less than 6 months after administrating therapeutic RAI; (3) no uptake present on a diagnostic RAI scan in the presence of otherwise detectable disease; (4) uptake is present in some, but not all, tumor foci on post-RAI scan [1] . The outcomes of an RAI scan are influenced by imaging preparation procedures and protocols. Moreover, therapeutic response to RAI is often heterogeneous, reflecting a wide spectrum of responsiveness among patients. Importantly, RAI avidity in DTCscan be modulated by pharmacological interventions. Therefore, the definition of RAI-R DTCs remains dynamic and is expected to evolve further, driven by advances in RAI imaging techniques and the development of neoadjuvant therapies that can resensitize DTCs to RAI [2]. RAI-R DTC is caused by the loss of key biological characteristics in its originating thyroid follicular cells, notably the iodide-metabolizing machinery [3] . The use of targeted pharmacologic agents prior to therapeutic RAI administration is a fascinating strategy for elevating the differentiation status of DTC, thereby restoring RAI avidity and improving tumor response to RAI [4] . Over the past decades, substantial progress has been made in elucidating the molecular pathogenesis of RAI-R DTC, highlighting the role of genetic and epigenetic alterations and dysregulated signaling pathways [5,6]. Among these, genetic alterations in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathways, caused by acquired point mutations such as BRAF or RAS, or by gene fusions involving RET or neurotrophic tyrosine receptor kinases (NTRKs), are major drivers of pathogenesis and RAI refractoriness through diminished expression or mislocalization of the sodium/iodide symporter [6,7] . The Cancer Genome Atlas Research Network reported that BRAF-like TCs exhibit a lower differentiation score and reduced expression of iodidemetabolizing genes, accompanied by higher activation of the Received: 12 November 2025, Accepted: 17 November 2025 Corresponding author: Byeong-Cheol Ahn Department of Nuclear Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Korea Tel: +82-53-420-5583, Fax: +82-53-200-6447, [E-mail:](E-mail: abc2000@knu.ac.kr)[ abc2000@knu.ac.kr](E-mail: abc2000@knu.ac.kr)[ ](E-mail: abc2000@knu.ac.kr)*These authors contributed equally to this work. Copyright © 2025 Korean Endocrine Society This is an Open Access article distributed under the terms of the Creative Commons Attribution No

FAQs

How do the 2025 ATA guidelines define radioactive-iodine refractory (RAI-R) differentiated thyroid cancer?

RAI-R is defined using criteria such as lack of 131I uptake on post-RAI scans despite known disease, progression within 6 months after therapeutic RAI, absent uptake on diagnostic RAI scans when disease is detectable, and partial uptake across tumor foci.

Why is the RAI-R definition described as dynamic?

The outcomes of RAI scanning depend on imaging preparation procedures and protocols, and therapeutic responses to RAI vary among patients. Pharmacologic interventions and neoadjuvant approaches can also modulate radioiodine avidity.

What molecular mechanisms contribute to RAI refractoriness?

RAI refractoriness is tied to loss of key biological features of thyroid follicular cells, especially the iodide-metabolizing machinery. Genetic and epigenetic alterations, including MAPK and PI3K-AKT pathway dysregulation from mutations (e.g., BRAF, RAS) or RET/NTRK fusions, reduce sodium/iodide symporter expression or mislocalize it.

Sep 29, 2026

Uploaded by Riley