Clinical Implications of Dually Targeting the Sodium Iodide Symporter in Canonical and Non-Canonical Settings

Exploitation of the sodium iodide symporter (NIS) in therapeutic and imaging settings often fails due to diminished activity. Here, we targeted the ER-associated degradation of NIS mediated by valosin-containing protein (VCP), a key regulator of protein homeostasis. Although rationally designed VCP inhibitors increased NIS activity, Cu(DDC)2 – a copper metabolite of disulfiram – gave the greatest induction of radioiodide uptake across thyroid and breast cancer cells, as well as thyrocytes from hyperplastic patients. Mechanistically, Cu(DDC)2 elicited a dual effect on NIS function, targeting VCP as well as inducing potent transcriptional responses. BALB/c mice demonstrated enhanced thyroidal radionuclide uptake correlating with NIS expression, whilst combining Cu(DDC)2 with the HDAC inhibitor SAHA doubled uptake in orthotopic breast tumors. RNA-seq analysis facilitated a robust classifier for stratifying recurrence risk of radioiodide-treated patients. Collectively, our study provides mechanistic understanding of new strategies to stimulate NIS activity in vivo, with potential clinical application for improving radionuclide-based therapies.