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
Metrics: PDF 1402 views | HTML 2314 views | ?
Ji Min Oh1,2,*, Senthilkumar Kalimuthu1, Prakash Gangadaran1, Se Hwan Baek1, Liya Zhu1, Ho Won Lee1, Ramya Lakshmi Rajendran1, Chae Moon Hong1, Shin Young Jeong1, Sang-Woo Lee1, Jaetae Lee1 and Byeong-Cheol Ahn1,2
1Department of Nuclear Medicine, Kyungpook National University School of Medicine and Hospital, Daegu 41944, Republic of Korea
2BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University School of Medicine and Hospital, Daegu 41944, Republic of Korea
Byeong-Cheol Ahn, email: [email protected]
Keywords: anaplastic thyroid cancer; sodium iodide symporter; tyrosine kinase inhibitor; radioactive-iodine therapy; high-throughput screening
Received: November 28, 2017 Accepted: December 21, 2017 Published: January 11, 2018
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 tumour in vivo. In conclusion, we successfully established a novel high-throughput NIS enhancer screening platform to excavate a NIS enhancer and identified K905-0266 TKI among TKI candidates and it’s proven to increase the endogenous NIS expression and therapeutic efficacy of RAI in ATC. These findings suggest that a novel high-throughput NIS enhancer screening platform is useful for selecting of NIS promoter enhancers. In addition, K905-0266 TKI can be used to re-induce endogenous NIS expression and recover RAI therapy in ATC.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.