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

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Anaplastic thyroid carcinoma (ATC) is notoriously resistant to radioiodine therapy due to poor iodine metabolism.
• Targeting key signaling pathways may restore radioiodine uptake and sensitivity.

Purpose of the Study:

• To investigate the efficacy of inhibiting mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways to enhance radioiodine uptake in ATC.
• To evaluate the therapeutic potential of MEK inhibition combined with radioiodine treatment in preclinical ATC models.

Main Methods:

• Human ATC cell lines were treated with MAPK and PI3K pathway inhibitors to assess effects on sodium-iodine symporter (NIS) transcription and iodine uptake.
• Thyrocyte-specific BRAF^V600E PIK3CA^H1047R mutant mice received MEK inhibitor treatment followed by radioiodine, with tumor burden monitored via ultrasound.

Main Results:

• MEK or BRAF inhibition, alone or with PI3K inhibition, increased NIS transcription and iodine uptake in ATC cell lines.
• In vivo, MEK inhibition upregulated NIS transcription and led to a stable reduction in tumor burden when preceding radioiodine administration.
• BRAF or PI3K inhibition alone did not yield similar therapeutic effects in vivo.

Conclusions:

• MEK inhibition effectively induces radioiodine uptake in both in vitro and in vivo ATC models.
• Pre-treatment with a MEK inhibitor before radioiodine therapy demonstrates significant potential for clinical translation.
• This strategy could provide a vital new treatment option for patients suffering from radioiodine-refractory anaplastic thyroid carcinoma.