Journal
JOURNAL OF NUCLEAR MEDICINE
Volume 60, Issue 7, Pages 917-923Publisher
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.118.216721
Keywords
drug resistance; NIS; targeted therapy; differentiation
Funding
- Swiss National Science Foundation [31003A_149824/1]
- Swiss National Science Foundation grant NCCR-TransCure
- Swiss National Science Foundation (SNF) [31003A_149824] Funding Source: Swiss National Science Foundation (SNF)
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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.
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