MAPK Inhibitors Enhance HDAC Inhibitor-Induced Redifferentiation in Papillary Thyroid Cancer Cells Harboring BRAF(V600E): An In Vitro Study

Clinical efficacy of redifferentiation therapy with histone deacetylase inhibitor (HDACi) for lethal radioiodine-refractory papillary thyroid cancer (RR-PTC) is urgently needed to be improved. Given that the impairment of histone acetylation is a mechanism in BRAF(V600E)-mitogen-activated protein kinase (MAPK)-induced aberrant silencing of thyroid iodine-metabolizing genes, dual inhibition of HDAC and MAPK may produce a more favorable effect. In this study, we treated BRAF(V600E)-mutant (BCPAP and K1) and BRAF-wild-type (BHP 2-7) cells with HDACi (panobinostat) and MAPK inhibitor (dabrafenib or selumetinib), alone or in combination, and we tested the expression of iodine- and glucose-metabolizing genes, radioiodine uptake and efflux, and toxicity. We found that panobinostat alone increased iodine-metabolizing gene expression, promoted radioiodine uptake and toxicity, and suppressed GLUT1 expression in all the cells. However, MAPKi (dabrafenib or selumetinib) induced these effects only in BRAF(V600E)-mutant cells. Combined treatment with panobinostat and MAPKi (dabrafenib or selumetinib) displayed a more robust BRAF(V600E)-dependent redifferentiation effect than panobinostat alone via further improving the acetylation level of histone at the sodium-iodide symporter (NIS) promoter. In conclusion, MAPK inhibitors enhance HDACi-induced redifferentiation in PTC cells harboring BRAF(V600E), warranting animal and clinical trials.