MEK抑制剂诱导碘难治性甲状腺癌I-131摄取新机制探索及临床疗效预测液体生物标志物筛选研究

碘难治性甲状腺癌（RAIR-DTC）对I-131不敏感，预后差。MEK抑制剂能恢复NIS表达并增加放射性碘摄取（RAIU）并取得良好临床前研究结果，但临床分化治疗效果仍欠佳，对分化疗效预测缺乏准确检测指标，寻找监测MEKi诱导RAIU增加简单易测的液体标志物是RAIR-DTC研究方向。我们前期通过MEKi诱导甲状腺癌分化研究时在筛选出了与NIS启动子密切相关8个转录因子（TFs），基于此，通过机制研究试图进一步寻找增加RAIU及NIS表达潜在靶点，为MEK抑制剂对RAIR-DTC分化治疗效果提升提供依据。在发现MEKi增加体内外DTC模型RAIU基础上筛选出了47个与NIS表达相关分泌蛋白基因，以此基础，分析前10个高度相关基因在Tg-BRAFV600E小鼠血液中与SPECT检测的RAIU相关性，进而找到反应NIS介导RAIU增加的液体标志物，为临床分化治疗疗效监控提供参考。

Iodine-refractory DTC (RAIR-DTC) patients with metastatic tumors that do not trap sufficient radioactive iodine (RAI) I-131 and also are not responsive to 131I therapy, which are also associated with worse prognosis. MEK inhibitors (MEKi) can restore NIS expression and increase radioactive iodine uptake (RAIU), which achieve good preclinical results. However, their clinical differentiation therapeutic efficacy is still not satisfactory as a new option for subsequent treatment for RAIR-DTC patients. At the same time, there are still no biomarkers for accurately predicting the differentiation therapeutic efficacy of MEKi. Finding practical and convenient-to-measure liquid biomarkers to monitor the increasing of RAIU induced by MEKi is the new direction of RAIR-DTC study. Our previous study found that 8 transcription factors closely related with NIS promotor when radioiodine-refractory thyroid cancer treated by MEKi. Based on this, we attempted to further find potential therapeutic targets for increasing of RAIU and the expression of NIS through mechanism studies, which could provide theoretical basis for improving the differentiation efficacy of MEKi inhibitors on RAIR-DTC. In addition, we have also screened out 47 secreted protein genes related to NIS expression based on the discovery that MEKi increased thyroid cancer and cells model RAIU in vitro and in vivo. Based on this result, the correlation in the upper 10 highly relevant genes expression in Tg-BRAFV600E mice blood with SPECT RAIU will be investigated and then find the liquid biomarker. Consequently, liquid biomarkers closely associated with the increase of NIS mediated RAIU could be found and verified in subsequent clinical practice, which providing a new reference for monitoring clinical differentiation therapeutic efficacy of MEKi.