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.