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

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 BRAF(V600E) PIK3CA(H1047R) 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 BRAF(V600E) 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.