From the Guidelines
The pathophysiology of RAI-refractory DTCs is characterized by multiple molecular alterations, including genetic mutations, epigenetic modifications, and tumor dedifferentiation, which lead to loss of iodine uptake and metabolism capabilities. These cancers develop resistance through several key mechanisms, including downregulation of the sodium-iodide symporter (NIS) and other iodine-metabolizing proteins like thyroid peroxidase (TPO) and thyroglobulin (Tg) due to genetic mutations in the MAPK pathway, such as BRAF V600E, RAS, and RET/PTC rearrangements 1. Epigenetic modifications, including DNA methylation and histone deacetylation, also silence genes essential for iodine metabolism. Tumor dedifferentiation leads to progressive loss of thyroid-specific functions, including iodine uptake. Additionally, tumor heterogeneity plays a significant role, as RAI-avid and RAI-refractory cells can coexist within the same tumor or across metastatic sites. Microenvironmental factors, including hypoxia and inflammation, further contribute to RAI refractoriness by altering gene expression patterns. The PI3K/AKT/mTOR pathway activation also promotes resistance by interfering with NIS trafficking to the cell membrane.
Some key points to consider in the pathophysiology of RAI-refractory DTCs include:
- Genetic mutations in the MAPK pathway, such as BRAF V600E, RAS, and RET/PTC rearrangements, which downregulate NIS and other iodine-metabolizing proteins 1
- Epigenetic modifications, including DNA methylation and histone deacetylation, which silence genes essential for iodine metabolism
- Tumor dedifferentiation, which leads to progressive loss of thyroid-specific functions, including iodine uptake
- Tumor heterogeneity, which allows RAI-avid and RAI-refractory cells to coexist within the same tumor or across metastatic sites
- Microenvironmental factors, including hypoxia and inflammation, which contribute to RAI refractoriness by altering gene expression patterns
- PI3K/AKT/mTOR pathway activation, which promotes resistance by interfering with NIS trafficking to the cell membrane
Understanding these mechanisms has led to therapeutic strategies aimed at redifferentiation, such as MEK inhibitors (selumetinib, trametinib) and BRAF inhibitors (dabrafenib, vemurafenib), which can restore iodine uptake in some patients by inhibiting the MAPK pathway and reactivating NIS expression 1. These molecular insights are crucial for developing targeted approaches to overcome RAI refractoriness in DTC patients.
From the FDA Drug Label
14 CLINICAL STUDIES
A multicenter, randomized (2:1), double-blind, placebo-controlled study (SELECT; NCT01321554) was conducted in 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months prior to randomization, confirmed by independent radiologic review Radioactive iodine (RAI)-refractory was defined as 1 or more measurable lesions with no iodine uptake on RAI scan, iodine uptake with progression within 12 months of RAI therapy, or having received cumulative RAI activity >600 mCi (22 GBq) with the last dose administered at least 6 months prior to study entry
The pathophysiology of RAI-Refractory DTCs is not directly addressed in the provided drug label. However, it can be inferred that RAI-Refractory DTCs are characterized by:
- Loss of iodine uptake: Measurable lesions with no iodine uptake on RAI scan
- Progression despite RAI therapy: Iodine uptake with progression within 12 months of RAI therapy
- High cumulative RAI activity: Having received cumulative RAI activity >600 mCi (22 GBq) with the last dose administered at least 6 months prior to study entry The exact mechanisms underlying the development of RAI-Refractory DTCs are not explicitly stated in the provided text, and therefore, no conclusion can be drawn about the pathophysiology of this condition based on this information alone 2.
From the Research
Pathophysiology of RAI-Refractory DTCs
The pathophysiology of RAI-refractory differentiated thyroid cancers (DTCs) is complex and involves multiple molecular mechanisms.
- Genetic aberrations, such as BRAF, RAS, and RET/PTC rearrangements, play a significant role in the onset, progression, and dedifferentiation of DTCs 3, 4, 5.
- These genetic alterations activate the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways, leading to a decrease in sodium iodide symporter (NIS) expression and impaired iodine uptake 3, 5.
- The reduced expression of NIS and other iodide-handling genes results in resistance to radioactive iodine (RAI) therapy, making it challenging to treat RAI-refractory DTCs 4, 5.
- The absence of the sodium iodide transporter in the basement membrane of thyroid follicular cells also contributes to the development of RAI-refractory DTCs 4.
Molecular Mechanisms
The molecular mechanisms underlying RAI-refractory DTCs involve:
- Aberrant activation of signaling pathways, including MAPK and PI3K/AKT, which lead to the downregulation of thyroid-specific genes, including NIS 3, 5.
- Genetic mutations and rearrangements, such as BRAF and RET/PTC, which contribute to the dedifferentiation of DTCs and the development of RAI resistance 3, 4, 5.
- Impaired targeting of NIS to the cell membrane, which reduces iodine uptake and contributes to RAI resistance 3.
Therapeutic Implications
Understanding the pathophysiology of RAI-refractory DTCs is crucial for the development of effective therapeutic strategies.
- Targeting the molecular mechanisms underlying RAI resistance, such as the MAPK and PI3K/AKT signaling pathways, may help restore NIS expression and iodine uptake 3, 5.
- Multikinase inhibitors and other drugs that regulate these kinases or signaling pathways have shown promise in clinical and preclinical trials 4, 6.
- Redifferentiation therapy, which aims to restore the expression of iodine-metabolizing genes, including NIS, may also be an effective approach for treating RAI-refractory DTCs 5.