Advanced radioiodine-refractory differentiated thyroid cancer: the sodium iodide symporter and other emerging therapeutic targets

Lancet Diabetes Endocrinol. 2014 Oct;2(10):830-42. doi: 10.1016/S2213-8587(14)70051-8. Epub 2014 Jun 2.


Approximately 30% of patients with advanced, metastatic differentiated thyroid cancer have radioiodine-refractory disease, based on decreased expression of the sodium iodide symporter SLC5A5 (NIS), diminished membrane targeting of NIS, or both. Patients with radioiodine-refractory disease, therefore, are not amenable to (131)I therapy, which is the initial systemic treatment of choice for non-refractory metastatic thyroid cancer. Patients with radioiodine-refractory cancer have historically had poor outcomes, partly because these cancers often respond poorly to cytotoxic chemotherapy. In the past decade, however, considerable progress has been made in delineating the molecular pathogenesis of radioiodine-refractory thyroid cancer. As a result of the identification of key genetic and epigenetic alterations and dysregulated signalling pathways, multiple biologically targeted drugs, in particular tyrosine-kinase inhibitors, have been evaluated in clinical trials with promising results and have begun to meaningfully impact clinical practice. In this Review, we summarise the current knowledge of the molecular pathogenesis of advanced differentiated thyroid cancer and discuss findings from clinical trials of targeted drugs in patients with radioiodine-refractory disease. Additionally, we focus on the molecular basis of loss of NIS expression, function, or both in refractory disease, and discuss preclinical and clinical data on restoration of radioiodine uptake.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Clinical Trials as Topic
  • Humans
  • Iodine Radioisotopes / therapeutic use
  • Signal Transduction / drug effects*
  • Symporters / drug effects*
  • Thyroid Neoplasms / drug therapy*
  • Thyroid Neoplasms / metabolism*
  • Thyroid Neoplasms / radiotherapy


  • Antineoplastic Agents
  • Iodine Radioisotopes
  • Symporters
  • sodium-iodide symporter