MEK Inhibition Induces Therapeutic Iodine Uptake in a Murine Model of Anaplastic Thyroid Cancer

J Nucl Med. 2019 Jul;60(7):917-923. doi: 10.2967/jnumed.118.216721. Epub 2018 Nov 21.


Anaplastic thyroid carcinoma (ATC) is refractory to radioiodine therapy in part because of impaired iodine metabolism. We targeted the mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3'K) pathways with the intent to induce radioiodine uptake for radioiodine treatment of ATC. Methods: Human ATC cells were used to evaluate the ability of pharmacologic inhibition of the mitogen-activated protein kinase and PI3'K pathways to induce radioiodine uptake. Thyrocyte-specific double-mutant BRAFV600E PIK3CAH1047R mice were treated with a MEK inhibitor followed by radioiodine treatment, and tumor burden was monitored by ultrasound imaging. Results: ATC cell lines showed an increase in sodium-iodine symporter transcription when treated with a MEK or BRAFV600E inhibitor alone and in combination with PI3'K inhibitor. This translated into a dose-dependent elevation of iodine uptake after treatment with a MEK inhibitor alone and in combination with a PI3'K inhibitor. In vivo, MEK inhibition but not BRAF or PI3'K inhibition upregulated sodium-iodine symporter transcription. This translated into a stable reduction of tumor burden when mice were treated with a MEK inhibitor before radioiodine administration. Conclusion: This study confirms the ability of MEK inhibition to induce iodine uptake in in vitro and in vivo models of ATC. The approach of using a MEK inhibitor before radioiodine treatment could readily be translated into clinical practice and provide a much-needed therapeutic option for patients with ATC.

Keywords: NIS; differentiation; drug resistance; targeted therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / drug effects
  • Cell Line, Tumor
  • Disease Models, Animal
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Iodine Radioisotopes / metabolism*
  • Iodine Radioisotopes / therapeutic use
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Protein Kinase Inhibitors / pharmacology*
  • RNA, Messenger / genetics
  • Symporters / genetics
  • Thyroid Carcinoma, Anaplastic / genetics
  • Thyroid Carcinoma, Anaplastic / metabolism*
  • Thyroid Carcinoma, Anaplastic / pathology
  • Thyroid Carcinoma, Anaplastic / radiotherapy
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism*
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / radiotherapy
  • Transcription, Genetic / drug effects


  • Iodine Radioisotopes
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Symporters
  • sodium-iodide symporter
  • Mitogen-Activated Protein Kinase Kinases