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

Abstract

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 3kinase (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.

Synergy of GSK-J4 With Doxorubicin in KRAS-Mutant Anaplastic Thyroid Cancer

“…Additionally, 8505C and 8305C cells have BRAF gene mutations (Hoffmann et al, 2006;Sasanakietkul et al, 2018). Many new studies have been carried out on ATC patients with BRAF mutations, such as targeted therapy (Iyer et al, 2018;Knauf et al, 2018;Subbiah et al, 2018;ElMokh et al, 2019) and immunotherapy (Cabanillas et al, 2018). Although dabrafenib combined with trametinib has been widely accepted as an effective method for the treatment of BRAF mutation, there is no consensus that this therapy can be used for the treatment of KRAS mutant patients.…”

Redifferentiation of radioiodine-refractory thyroid cancers

“…Concerning undifferentiated thyroid cancers, namely ATC, hope for successful redifferentiation comes from a mouse model of lethally aggressive thyroid cancer, harboring BRAF V600E and PIK3CA H1047R mutations, demonstrating that MEK inhibition for only 10 days could increase radioiodine uptake, which could then translate into a stable and profound reduction in tumor burden (ElMokh et al 2019).…”

<p>Physiological and Pathophysiological Roles of Ion Transporter-Mediated Metabolism in the Thyroid Gland and in Thyroid Cancer</p>

“…57 Furthermore, EI Mokh's group demonstrated that by inhibiting NIS-related regulators (BRAF-V600E, MAPK, PI3K), iodine uptake levels in TC could be effectively promoted. 58 To date, preclinical and clinical studies on NIS as a therapeutic target have been conducted, some of which have been selected and are presented in Table 1. It can be concluded that NIS plays a significant role in TC; its aberrant expression in TC is caused by many factors and leads to abnormal iodine metabolism, meaning that radioactive iodide ions cannot be effectively taken up, thus affecting the prognosis of TC.…”