Reverting iodine avidity of radioactive-iodine refractory thyroid cancer with a new tyrosine kinase inhibitor (K905-0266) excavated by high-throughput NIS (sodium iodide symporter) enhancer screening platform using dual reporter gene system

Oncotarget
Ji Min OhByeong-Cheol Ahn

Abstract

Radioactive-iodine (RAI) therapy is typically unprevailing as anaplastic thyroid cancer (ATC) management, owing to the decrease in the endogenous sodium iodide symporter (NIS) expression. Therefore, new strategies for NIS re-induction are required to improve the efficacy of RAI therapy in ATC. In this study, we developed a novel high-throughput NIS enhancer screening platform using a dual reporter gene system to identify a potent tyrosine kinase inhibitor (TKI) and selected a new hit compound, K905-0266 TKI. The effects of K905-0266 TKI treatment was validated as RAI accumulation, changes in signalling pathway related to thyroid pathogenesis, and cytotoxicity of RAI depending on re-induction of endogenous NIS expression in ATC. Furthermore, we evaluated enhancement of NIS promoter and therapeutic efficacy of RAI in ATC tumour xenograft mice. After K905-0266 TKI treatment, the expression of endogenous NIS was significantly increased, while phosphorylated-ERK was decreased. In addition, the thyroid-metabolising protein expressions were upregulated and increased of RAI accumulation and its therapeutic effects in ATC. Moreover, K905-0266 TKI increased therapeutic efficacy of RAI in ATC tumourin vivo. In conclusion, we successfully ...Continue Reading

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Citations

Mar 20, 2020·Journal of Drug Targeting·Senthilkumar KalimuthuByeong-Cheol Ahn
Aug 6, 2020·Cancers·Mohammad Al-JundiJoanna Klubo-Gwiezdzinska
Jul 9, 2021·The Journal of Clinical Investigation·Young Ah LeeYoung Joo Park

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Methods Mentioned

BETA
fluorescence imaging
FACS
Confocal microscopy
xenograft
protein assay
electrophoresis

Software Mentioned

GraphPad
GraphPad Prism

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