An emerging role for proteostasis modulators targeting NIS activity to enhance radioiodide therapy in thyroid cancer

Introduction: New therapeutic strategies are urgently needed to improve radioiodide (RAI) uptake and efficiently ablate thyroid cancer cells, thereby reducing the risk of recurrent disease. We recently utilised high throughput screening and identified FDA-approved compounds capable of inducing sodium iodide symporter (NIS) function to enhance iodide uptake. Categorisation revealed a high proportion of drugs that modulate proteostasis, with 6 of the top 15 targeting activity of VCP–a critical component of the proteasome system. A better understanding of how proteostasis genes such as VCP modulate NIS function is now needed prior to clinical evaluation.

Methods: NanoBiT assays were used to assess the stringency of NIS:VCP interaction. NIS function was monitored by RAI (^125I) uptake assays. The Cancer Genome Atlas (TCGA) was appraised for proteostasis genes.

Results: We undertook rigorous evaluation of proteostasis inhibitors CB-5083 and disulfiram to understand their mechanistic impact on NIS function. CB-5083 and disulfiram induced NIS expression and ¹²⁵I uptake in multiple cell types (1.5-5-fold), including human primary thyrocytes. Importantly, NanoBiT showed that CB-5083 significantly decreased VCP binding to NIS. In contrast disulfiram failed to impact stringency of the NIS:VCP interaction but retained the ability to enhance NIS function in VCP-ablated thyroid cells. Disulfiram also failed to impact expression of autophagy marker LC3B-II but increased p62, indicating its effect on NIS was likely via VCP-independent proteasomal pathways. We next appraised TCGA and identified a 13-proteostasis gene riskscore classifier, including VCP, as an independent predictor of recurrence in RAI-treated papillary thyroid cancer (PTC). Critically, the predictive model showed a significantly worse prognosis for high-risk RAI-treated PTC [Hazard Ratio=35.9, 95%CI 4.8-267.4; P < 0.001;n = 137].

Conclusions: These results demonstrate differential mechanisms of emerging proteostasis modulators that target NIS activity to enhance radioiodide uptake. We further reveal the clinical relevance of proteostasis genes associated with an increased risk of recurrence.