El Mokh, Oussama; Taelmann, Vincent; Radojewski, Piotr; Rölli, Matthias Andreas; Stooss, Amandine; Dumont, Rebecca A; Dettmer, Matthias; Phillips, Wayne; Walter, Martin Alexander; Charles, Roch-Philippe (2019). MEK inhibition induces therapeutic iodine uptake in a murine model of anaplastic thyroid cancer. Journal of nuclear medicine, 60(7), pp. 917-923. Society of Nuclear Medicine 10.2967/jnumed.118.216721
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JNuclMed-2018-ElMokh-jnumed.118.216721.pdf - Accepted Version Available under License Publisher holds Copyright. Download (7MB) | Preview |
RATIONALE
Anaplastic thyroid carcinoma (ATC) is refractory to radioiodine therapy in part due to impaired iodine metabolism. We targeted the MAPK and PI3'K pathways with the intent to induce radioiodine uptake for radioiodine treatment of ATC. Human ATC cells were used to evaluate the ability of pharmacological inhibition of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase 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. 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 following treatment with a MEK inhibitor alone and in combination with a PI3'K inhibitor. In vivo, MEK inhibition but not BRAF nor 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 prior to radioiodine administration. 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.
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