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

Martin Read, Katie Brookes, Caitlin Thornton, Alice Fletcher, Hannah Nieto, Mohammed Alshahrani, Rashida Khan, Patricia Borges de Souza, Ling Zha, Jamie Webster, Luke Alderwick, Moray Campbell, Kristien Boelaert, Vicki Smith, Christopher McCabe

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The 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 riskscore 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.
Original languageEnglish
Pages (from-to)1-23
Number of pages23
JournalCell Chemical Biology
Publication statusPublished - 13 Sept 2021


  • NIS
  • VCP
  • autophagy
  • drug screening
  • proteasome
  • protein homeostasis
  • radioiodide
  • recurrence
  • risk score
  • thyroid cancer


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