Combined Vorinostat and Chloroquine Inhibit Sodium Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo

TY - JOUR

T1 - Combined Vorinostat and Chloroquine Inhibit Sodium Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo

AU - Read, Martin L

AU - Brookes, Katie

AU - Zha, Ling

AU - Manivannan, Selvambigai

AU - Kim, Jana

AU - Kocbiyik, Merve

AU - Fletcher, Alice

AU - Gorvin, Caroline M

AU - Firth, George

AU - Fruhwirth, Gilbert O

AU - Nicola, Juan P

AU - Jhiang, Sissy

AU - Ringel, Matthew D

AU - Campbell, Moray J

AU - Sunassee, Kavitha

AU - Blower, Philip J

AU - Boelaert, Kristien

AU - Nieto, Hannah R

AU - Smith, Vicki E

AU - McCabe, Christopher J

PY - 2023/11/3

Y1 - 2023/11/3

N2 - PURPOSE: Patients with aggressive thyroid cancer are frequently failed by the central therapy of ablative radioiodide (RAI) uptake, due to reduced plasma membrane (PM) localization of the sodium/iodide symporter (NIS). We aimed to understand how NIS is endocytosed away from the PM of human thyroid cancer cells, and whether this was druggable in vivo.EXPERIMENTAL DESIGN: Informed by analysis of endocytic gene expression in patients with aggressive thyroid cancer, we used mutagenesis, NanoBiT interaction assays, cell surface biotinylation assays, RAI uptake and NanoBRET to understand the mechanisms of NIS endocytosis in transformed cell lines and patient-derived human primary thyroid cells. Systemic drug responses were monitored via 99mTc pertechnetate gamma counting and gene expression in BALB/c mice.RESULTS: We identify an acidic dipeptide within the NIS C-terminus which mediates binding to the σ2 subunit of the Adaptor Protein 2 (AP2) heterotetramer. We discovered that the FDA-approved drug chloroquine modulates NIS accumulation at the PM in a functional manner that is AP2 dependent. In vivo, chloroquine treatment of BALB/c mice significantly enhanced thyroidal uptake of 99mTc pertechnetate in combination with the histone deacetylase (HDAC) inhibitor vorinostat/ SAHA, accompanied by increased thyroidal NIS mRNA. Bioinformatic analyses validated the clinical relevance of AP2 genes with disease-free survival in RAI-treated DTC, enabling construction of an AP2 gene-related risk score classifier for predicting recurrence.CONCLUSIONS: NIS internalisation is specifically druggable in vivo. Our data therefore provide new translatable potential for improving RAI therapy using FDA-approved drugs in patients with aggressive thyroid cancer.

AB - PURPOSE: Patients with aggressive thyroid cancer are frequently failed by the central therapy of ablative radioiodide (RAI) uptake, due to reduced plasma membrane (PM) localization of the sodium/iodide symporter (NIS). We aimed to understand how NIS is endocytosed away from the PM of human thyroid cancer cells, and whether this was druggable in vivo.EXPERIMENTAL DESIGN: Informed by analysis of endocytic gene expression in patients with aggressive thyroid cancer, we used mutagenesis, NanoBiT interaction assays, cell surface biotinylation assays, RAI uptake and NanoBRET to understand the mechanisms of NIS endocytosis in transformed cell lines and patient-derived human primary thyroid cells. Systemic drug responses were monitored via 99mTc pertechnetate gamma counting and gene expression in BALB/c mice.RESULTS: We identify an acidic dipeptide within the NIS C-terminus which mediates binding to the σ2 subunit of the Adaptor Protein 2 (AP2) heterotetramer. We discovered that the FDA-approved drug chloroquine modulates NIS accumulation at the PM in a functional manner that is AP2 dependent. In vivo, chloroquine treatment of BALB/c mice significantly enhanced thyroidal uptake of 99mTc pertechnetate in combination with the histone deacetylase (HDAC) inhibitor vorinostat/ SAHA, accompanied by increased thyroidal NIS mRNA. Bioinformatic analyses validated the clinical relevance of AP2 genes with disease-free survival in RAI-treated DTC, enabling construction of an AP2 gene-related risk score classifier for predicting recurrence.CONCLUSIONS: NIS internalisation is specifically druggable in vivo. Our data therefore provide new translatable potential for improving RAI therapy using FDA-approved drugs in patients with aggressive thyroid cancer.

U2 - 10.1158/1078-0432.CCR-23-2043

DO - 10.1158/1078-0432.CCR-23-2043

M3 - Article

C2 - 37921808

SN - 1078-0432

SP - Volume 30, Pages 1352–1366

JO - Clinical cancer research : an official journal of the American Association for Cancer Research

JF - Clinical cancer research : an official journal of the American Association for Cancer Research

M1 - https://doi.org/10.1158/1078-0432.CCR-23-2043

ER -