MAPK pathway inhibitors enhance radioiodine sensitivity in anaplastic thyroid carcinoma through promoting NIS expression and ARF4-mediated NIS membrane transport

Objective: Anaplastic thyroid cancer (ATC) patient develops resistance to radioactive iodine (RAI) due to diminished sodium-iodide symporter (NIS) expression and mislocalization to the cell membrane. MAPK pathway inhibitors have demonstrated efficacy in enhancing RAI avidity in radioiodine-refractory papillary thyroid carcinoma and ATC. Elucidating this mechanism may lead to novel therapeutic approaches for ATC treatment. Methods: The cytotoxic effects of three MAPK pathway inhibitors (selumetinib, vemurafenib, dabrafenib) were assessed in ATC cell lines and xenograft models via viability assays and ¹⁸ F-FDG PET/CT. We investigated their impact on radioiodine metabolism by analyzing the expression of key genes (NIS, TSHR, and TPO) and trafficking regulators (ARF4, PIGU, and β-catenin) via Western blotting, and assessing NIS localization and function through immunofluorescence and uptake assays. The protein interaction between NIS and ARF4 was examined via co-immunoprecipitation (co-IP) and immunofluorescence. Results: MAPK pathway inhibitors reduced the viability of ATC cell lines. ATC cells exhibited restored iodine metabolism-related gene expression after treatment, and pronounced increases in membrane-localized NIS were detected via the promotion of ARF4 expression. Furthermore, MAPK pathway inhibitors increased radioiodine uptake in ATC cells. Conclusion: The MAPK pathway inhibitors enhance NIS function through two mechanisms: upregulation of NIS expression and increased ARF4-mediated NIS membrane transport.