Targeting non-canonical pathways as a strategy to modulate the sodium iodide symporter

Martin L Read,Katie Brookes,Caitlin E.M Thornton,Alice Fletcher,Hannah R Nieto,Mohammed Alshahrani,Rashida Khan,Patricia Borges De Souza,Ling Zha,Jamie R.M Webster,Luke J Alderwick,Moray J Campbell,Kristien Boelaert,Vicki E Smith,Christopher J Mccabe

doi:10.1016/j.chembiol.2021.07.016

Martin L Read, Katie Brookes + Show 13 more

Open Access

https://doi.org/10.1016/j.chembiol.2021.07.016

Copy DOI

Abstract

SummaryThe sodium iodide symporter (NIS) functions to transport iodide and is critical for successful radioiodide ablation of cancer cells. Approaches to bolster NIS function and diminish recurrence post-radioiodide therapy are impeded by oncogenic pathways that suppress NIS, as well as the inherent complexity of NIS regulation. Here, we utilize NIS in high-throughput drug screening and undertake rigorous evaluation of lead compounds to identify and target key processes underpinning NIS function. We find that multiple proteostasis pathways, including proteasomal degradation and autophagy, are central to the cellular processing of NIS. Utilizing inhibitors targeting distinct molecular processes, we pinpoint combinatorial drug strategies giving robust >5-fold increases in radioiodide uptake. We also reveal significant dysregulation of core proteostasis genes in human tumors, identifying a 13-gene risk score classifier as an independent predictor of recurrence in radioiodide-treated patients. We thus propose and discuss a model for targetable steps of intracellular processing of NIS function.

Highlights

For $80 years, radioiodide (RAI) has been the central post-surgical treatment for patients with differentiated thyroid cancer (DTC)
Drug screening identifies novel compounds that alter surrogate NIS activity We first adapted and validated yellow fluorescent protein (YFP)iodide sensing to an high-throughput screening (HTS) of 1,200 drugs (Prestwick Chemical Library; 95% FDA approved) as outlined (Figures 1A–1C and S1A)
Increased NIS protein matched greater radioiodide uptake induced by these three drugs in 8505C-NIS cells (Figure 2E)

Summary

Introduction

For $80 years, radioiodide (RAI) has been the central post-surgical treatment for patients with differentiated thyroid cancer (DTC). At least 25% of DTC patients have radioiodide-refractory thyroid cancer, being unable to uptake adequate radioiodide for effective therapeutic ablation (Schlumberger et al, 2014). This is especially problematic for DTC patients with metastatic disease who have a life expectancy of 2.5–3.5 years (Lirov et al, 2017). Sodium iodide symporter (NIS) is the sole transporter responsible for specific cellular iodide uptake (Dai et al, 1996); exploitation of its function permits specific targeting of high-energy b-emitting 131I to destroy remaining thyroid cells post-surgery, and target metastases. The central mechanisms that underlie radioiodide refractoriness are decreased levels of NIS expression and/or its diminished targeting to the plasma membrane (PM)

Methods

Results

Discussion

Conclusion