Pathogenesis and Management Strategies in Radioiodine-Refractory Differentiated Thyroid Cancer: From Molecular Mechanisms Toward Therapeutic Approaches: A Comprehensive Review

Abstract

Thyroid cancer (TC) remains the most common cancer in endocrinology. Differentiated thyroid cancer (DTC), the most common type of TC, generally has a favorable outlook with conventional treatment, which typically includes surgery along with radioiodine (RAI) therapy and thyroid-stimulating hormone (TSH) suppression through thyroid hormone therapy. However, a small subset of patients (less than 5%) develop resistance to RAI. This resistance occurs due to the loss of Na/I symporter (NIS) activity, which is crucial for iodine absorption in thyroid cells. The decline in NIS activity appears to be due to gene modifications, reconfigurations with irregular stimulation of signaling pathways such as MAPK and PI3K/Akt pathways. These molecular changes lead to a diminished ability of DTC cells to concentrate iodine, which makes RAI therapy ineffective. As a consequence, patients with radioiodine-refractory DTC require alternative treatments. Therapy with tyrosine kinase inhibitors (TKIs) has emerged as the primary treatment option to inhibit proliferation and growth of RAIR-DTC, targeting the pathways responsible for tumor progression. In this article, we analyze molecular processes responsible for RAI resistance and explore both conventional and emerging therapeutic strategies for managing RAIR-DTC, aiming to improve patient outcomes.

Keywords: NIS; RAIR-DTC; differentiated thyroid cancer; iodine therapy; signal pathways; surgery; tyrosine kinase inhibitors.

Figure 3

FDA-approved TKIs for RAIR-DTC [112,121,123]. Abbreviations: FDA—Food and Drug Administration; c-MET—hepatocyte growth factor receptor or HGFR; c-KIT—stem cell factor receptor or SCFR; EGFR—epidermal growth factor receptor; FGFR—fibroblast growth factor receptor; FLT3—FMS-like tyrosine kinase 3 (or CD135); PDGFR—platelet-derived growth factor receptor; RET—ret proto-oncogene; RAF—rapidly accelerated fibrosarcoma; VEGFR—vascular endothelial growth factor receptor; DECISION ClinicalTrials.gov number, NCT00984282; SELECT ClinicalTrials.gov number, NCT01321554; COSMIC-311 ClinicalTrials.gov number NCT03690388.

Figure 4

Randomized control trial of FDA-approved TKIs for RAIR-DTC [112,121,123]. Abbreviations: FDA—Food and Drug Administration; DECISION ClinicalTrials.gov number, NCT00984282; SELECT ClinicalTrials.gov number, NCT01321554; COSMIC-311 ClinicalTrials.gov number NCT03690388.

Figure 1

MAPK pathway in PTC [29,30,59,60,61,62,63]. Abbreviations: BRAF—V-Raf mouse sarcoma virus oncogene homologous B1; MEK—mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MAPK—mitogen-activated protein kinase.

Figure 2

Treatment approach for advanced/metastatic DTC [1,28,30]. Abbreviations: RAI—radioactive iodine; RAI-avid—radioactive iodine-avid; TKI—tyrosine kinase inhibitor.