Abstract
Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.
Highlights
Radioactive iodine I-131 (RAI) is a cornerstone in the routine adjuvant management in patients with high-risk differentiated thyroid cancer (DTC) [1]; 5% to 15% of DTC and 50% of Cancers 2019, 11, 1382; doi:10.3390/cancers11091382 www.mdpi.com/journal/cancersCancers 2019, 11, 1382 metastatic DTCs are refractory to RAI treatment [2–4]
tyrosine kinase inhibitors (TKIs) have revolutionized the field of targeted therapy in RAI-R DTC patients, these agents are usually administered lifelong, and several drawbacks were associated with their long-term application
These results show the inhibitory effects of the aberrant tyrosine kinases on the immune system, indicating the potential of TKIs to reverse them, with the combination of TKIs and immune checkpoint inhibitors seemingly an attractive regimen for patients with RAI-R DTC
Summary
Radioactive iodine I-131 (RAI) is a cornerstone in the routine adjuvant management in patients with high-risk differentiated thyroid cancer (DTC) [1]; 5% to 15% of DTC and 50% of Cancers 2019, 11, 1382; doi:10.3390/cancers11091382 www.mdpi.com/journal/cancers. Cancers 2019, 11, 1382 metastatic DTCs are refractory to RAI treatment [2–4]. Patients with RAI-refractory (RAI-R) thyroid cancer have poor outcomes, with 5-year disease-specific survival rates of 60% to 70% [5] RAI-R metastatic thyroid cancer have the worst outcomes, with a 10-year survival rate of 10% [6]. With recent advances and developments in understanding of the oncogenic pathways involved in the development of thyroid cancers and the molecular basis of RAI refractoriness, targeted therapies are being developed and are showing promising results [7–10]. We review the molecular mechanisms underlying RAI refractoriness, describe targeted therapies that may overcome these mechanisms, and explore promising therapeutic regimens to improve outcomes in RAI-R thyroid cancers
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