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The BRAF(V600E) mutation is present in 62% of radioactive iodine-resistant thyroid tumors and is associated with downregulation of the sodium-iodide symporter (NIS) and thyroid stimulating hormone receptor (TSHr). We sought to evaluate the combined effect of BRAF inhibition and TSH supplementation on (131)I uptake of BRAF(V600E)-mutant human thyroid cancer cells.WRO cells (a BRAF(V600E)-mutant follicular-derived papillary thyroid carcinoma cell line) were transfected with small interfering RNA targeting BRAF for 72 h in a physiological TSH environment. NIS and TSHr expression were then evaluated at three levels: gene expression, protein levels, and (131)I uptake. These three main outcomes were then reassessed in TSH-depleted media and media supplemented with supratherapeutic concentrations of TSH.NIS gene expression increased 5.5-fold 36 h after transfection (P = 0.01), and TSHr gene expression increased 2.8-fold at 24 h (P = 0.02). NIS and TSHr protein levels were similarly increased 48 and 24 h after transfection, respectively. Seventy-two hours after BRAF inhibition, (131)I uptake was unchanged in TSH-depleted media, increased by 7.5-fold (P 0.01) in physiological TSH media, and increased by 9.1-fold (P0.01) in supratherapeutic TSH media.The combined strategy of BRAF inhibition and TSH supplementation results in greater (131)I uptake than when either technique is used alone. This represents a simple and feasible approach that may improve outcomes in patients with radioactive iodine-resistant thyroid carcinomas for which current treatment algorithms are ineffective.

argeting BRAFV600E using nanoliposomal-small nterfering RNA restores the expression of sodium iodide ymporter and increases the uptake of iodide in thyroid ancer cells aniel Buitrago MD, Hasan Aldailami BSC, Alexander Veach BSC, ilippo Filicori MD, Xavier M Keutgen MD, Mike Crowley BSC, oonsoo Jin SCD, Thomas J Fahey III MD, FACS, asa Zarnegar MD, FACS eill Cornell Medical College, New York, NY, Cornell University, thaca, NY and Memorial Sloan Kettering Cancer Center, New ork, NY