Weiwei Cheng1, Rengyun Liu1, Guangwu Zhu1, Hui Wang1, Mingzhao Xing1. 1. Laboratory for Cellular and Molecular Thyroid Research (W.C., R.L., G.Z., M.X.), Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; and Department of Nuclear Medicine (H.W.), Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
Abstract
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.
CONTEXT: Use of BRAFV600E 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 BRAFV600E and HDAC could be a more effective strategy. OBJECTIVES: The objective of the study was to test whether suppressing both BRAFV600E and HDAC could more effectively induce thyroid gene expression and RAI uptake in thyroid cancer cells. RESEARCH DESIGN: We tested the BRAFV600E 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 BRAFV600E. 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 BRAFV600E-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 BRAFV600E. Abundant sodium/iodide symporter protein expression in thyroid cancer cells under these conditions was confirmed by immunofluorescent microscopy. CONCLUSIONS: Simultaneously suppressing BRAFV600E 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 BRAFV600E alone. Triple combination of PLX4032, SAHA, and TSH is a specific robust regimen to restore RAI avidity in RAI-refractory BRAFV600E-positive thyroid cancer, which warrants clinical trials to confirm.
Authors: Jennifer A Woyach; Richard T Kloos; Matthew D Ringel; Daria Arbogast; Minden Collamore; James A Zwiebel; Michael Grever; Miguel Villalona-Calero; Manisha H Shah Journal: J Clin Endocrinol Metab Date: 2008-10-14 Impact factor: 5.958
Authors: Peng Hou; Dingxie Liu; Meiju Ji; Zhi Liu; James M Engles; Richard L Wahl; Mingzhao Xing Journal: PLoS One Date: 2009-07-10 Impact factor: 3.240
Authors: Alan L Ho; Ravinder K Grewal; Rebecca Leboeuf; Eric J Sherman; David G Pfister; Desiree Deandreis; Keith S Pentlow; Pat B Zanzonico; Sofia Haque; Somali Gavane; Ronald A Ghossein; Julio C Ricarte-Filho; José M Domínguez; Ronglai Shen; R Michael Tuttle; Steve M Larson; James A Fagin Journal: N Engl J Med Date: 2013-02-14 Impact factor: 91.245
Authors: Marie-Claude Hofmann; Muthusamy Kunnimalaiyaan; Jennifer R Wang; Naifa L Busaidy; Steven I Sherman; Stephen Y Lai; Mark Zafereo; Maria E Cabanillas Journal: Endocr Relat Cancer Date: 2022-09-14 Impact factor: 5.900