Title | Dual inhibition of BRAF and MEK increases expression of sodium iodide symporter in patient-derived papillary thyroid cancer cells in vitro. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Ullmann TM, Liang H, Moore MD, Al-Jamed I, Gray KD, Limberg J, Stefanova D, Buicko JL, Finnerty B, Beninato T, Zarnegar R, Min IM, Fahey TJ |
Journal | Surgery |
Volume | 167 |
Issue | 1 |
Pagination | 56-63 |
Date Published | 2020 01 |
ISSN | 1532-7361 |
Keywords | Adult, Age Factors, Aged, Antineoplastic Combined Chemotherapy Protocols, Chemoradiotherapy, Female, Gene Expression Regulation, Neoplastic, Humans, Imidazoles, Iodine Radioisotopes, Male, MAP Kinase Signaling System, Middle Aged, Mitogen-Activated Protein Kinase Kinases, Mutation, Oximes, Primary Cell Culture, Prospective Studies, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), Pyridones, Pyrimidinones, Radiation Tolerance, Symporters, Thyroid Cancer, Papillary, Thyroid Neoplasms, Tumor Cells, Cultured, Up-Regulation |
Abstract | BACKGROUND: The majority of papillary thyroid cancers are driven by acquired mutations typically in the BRAF or RAS genes that aberrantly activate the mitogen-activated protein kinase pathway. This process leads to malignant transformation, dedifferentiation, and a decrease in the expression of the sodium-iodide symporter (NIS; SLC5A5), which results in resistance to radioactive iodine therapy. We sought to determine whether inhibition of aberrant mitogen-activated protein kinase-signaling can restore NIS expression. METHODS: We prospectively developed cultures of papillary thyroid cancers derived from operative specimens and applied drug treatments for 24 hours. Samples were genotyped to identify BRAF and RAS mutations. We performed quantitative PCR to measure NIS expression after treatment. RESULTS: We evaluated 24 patient papillary thyroid cancer specimens; BRAF mutations were identified in 18 out of 24 (75.0%); 1 patient tumor had an HRAS mutation, and the remaining 5 were BRAF and RAS wildtype. Dual treatment with dabrafenib and trametinib increased NIS expression (mean fold change 4.01 ± 2.04, P < .001), and single treatment with dabrafenib had no effect (mean fold change 0.98 ± 0.42, P = .84). Tumor samples that had above-median NIS expression increases came from younger patients (39 vs 63 years, P < .05). CONCLUSION: Dual treatment with BRAF and MEK inhibitors upregulated NIS expression, suggesting that this treatment regimen may increase tumor iodine uptake. The effect was greatest in tumor cells from younger patients. |
DOI | 10.1016/j.surg.2019.04.076 |
Alternate Journal | Surgery |
PubMed ID | 31585718 |