Optimization And Mechanism Of Kinase Inhibitor-induced Redifferetiation Of Thyroid Carcinoma

Purpose:Redifferentiation therapy using MAPK inhibitor is a novel strategy for radioiodine-refractory differentiated thyroid carcinoma,but its objective response rate is relatively low due to reasons,such as drug resistance.Recently,MAPK rebound caused by BRAF/MEK inhibitor-induced activation of HER2/HER3 has been recognized.On the other hand,impairment of histone acetylation has also been revealed as a mechanism in BRAF^V600E/MAPK-induced aberrant silencing of thyroid iodine metabolizing genes.As such,combined strategy using MAPK inhibitors and HER inhibitor/histone deacetylation inhibitor?HDACI?may produce more significant redifferentiation effect.Methods:We chose three papillary thyroid carcinoma?PTC?cell lines,BCPAP,K1,BHP 2-7 cells,and carried out in vitro experiment such as RT-PCR,Western blot,immunofluorescence,radioisotope uptake/efflux,colongenic assay to test iodine and glucose metabolizing gene expression and radioiodine uptake of the cells when treated with MAPK inhibitors?dabrafenib/selumetinib?alone or in combination with HER inhibitor?lapatinib?or HDACI?panobinostat?.Results:Dabrafenib/selumetinib promoted expression of iodine metabolizing genes and radioiodine uptake and suppressed expression of GLUT1 in BCPAP and K1 cells.Such redifferetiation effect was further enhanced by combination with lapatinib or panobinostat.In BHP 2-7 cells,dabrafenib/selumetinib alone or combined with lapatinib showed no redifferetiation effect,while panobinostat could induce redifferetiation.Conclusions:Refined strategy using MAPK inhibitor in combination with HER inhibitor or HDACI in PTC cells harboring BRAF^V600E can produce more robust redifferentiation effect than MAPK inhibitor alone.