CONTEXT: Use of BRAF V600E inhibitors to restore thyroid iodide-handling gene 
expression and radioactive iodine (RAI) avidity is an attractive therapeutic 
strategy for RAI-refractory thyroid cancer, but recent initial clinical 
responses were modest. Given histone deacetylation at the sodium/iodide 
symporter promoter by histone deacetylase (HDAC) as a mechanism, simultaneously 
targeting BRAF V600E and HDAC could be a more effective strategy.
OBJECTIVES: The objective of the study was to test whether suppressing both BRAF 
V600E and HDAC could more effectively induce thyroid gene expression and RAI 
uptake in thyroid cancer cells.
RESEARCH DESIGN: We tested the BRAF V600E inhibitor PLX4032 (vemurafenib) and 
the HDAC inhibitor SAHA (vorinostat), two major anticancer drugs currently 
approved for clinical use, in inducing thyroid gene expression and RAI uptake in 
thyroid cancer cells.
RESULTS: PLX4032 alone induced a modest expression of thyroid genes and RAI 
uptake preferentially in thyroid cancer cells harboring BRAF V600E. SAHA showed 
an effect in a genetic-independent manner in all the cells. A robust synergistic 
effect on thyroid gene expression and RAI uptake was observed in BRAF 
V600E-positive thyroid cancer cells when the two inhibitors were simultaneously 
used. This was dramatically enhanced further by TSH; triple combination of 
PLX4032, SAHA, and TSH showed the most robust effect on thyroid gene expression 
and RAI uptake in cells harboring BRAF V600E. Abundant sodium/iodide symporter 
protein expression in thyroid cancer cells under these conditions was confirmed 
by immunofluorescent microscopy.
CONCLUSIONS: Simultaneously suppressing BRAF V600E and HDAC, particularly when 
cotreated with TSH, induced a far more robust expression of thyroid genes and 
RAI uptake in thyroid cancer cells than suppressing BRAF V600E alone. Triple 
combination of PLX4032, SAHA, and TSH is a specific robust regimen to restore 
RAI avidity in RAI-refractory BRAF V600E-positive thyroid cancer, which warrants 
clinical trials to confirm.