Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation

Abstract

Advanced human thyroid cancers, particularly those that are refractory to treatment with radioiodine (RAI), have a high prevalence of BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations. However, the degree to which these cancers are dependent on BRAF expression is still unclear. To address this question, we generated mice expressing one of the most commonly detected BRAF mutations in human papillary thyroid carcinomas (BRAF V600E ) in thyroid follicular cells in a doxycycline-inducible (dox-inducible) manner. Upon dox induction of BRAF V600E , the mice developed highly penetrant and poorly differentiated thyroid tumors. Discontinuation of dox extinguished BRAF V600E expression and reestablished thyroid follicular architecture and normal thyroid histology. Switching on BRAF V600E rapidly induced hypothyroidism and virtually abolished thyroid-specific gene expression and RAI incorporation, all of which were restored to near basal levels upon discontinuation of dox. Treatment of mice with these cancers with small molecule inhibitors of either MEK or mutant BRAF reduced their proliferative index and partially restored thyroid-specific gene expression. Strikingly, treatment with the MAPK pathway inhibitors rendered the tumor cells susceptible to a therapeutic dose of RAI. Our data show that thyroid tumors carrying BRAF V600E mutations are exquisitely dependent on the oncoprotein for viability and that genetic or pharmacological inhibition of its expression or activity is associated with tumor regression and restoration of RAI uptake in vivo in mice. These findings have potentially significant clinical ramifications.

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

“…BRAF V600E is an oncogenic protein with markedly elevated kinase activity that overactivates the MAPK pathway, especially ERK signaling transduction (Xing 2005, Chakravarty et al 2011. Here, we show that BRAF V600E mutation is associated with the highest levels of DIO3 expression, as compared with RET/PTC1 ( Fig.…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…For example, the thyroid volume of an adult 400-500 g rat varies between 35 and 70 lL (57). In addition to the thyroid gland itself, this approach has also been used to image metastases of thyroid cancer in mice (58).…”

Application of molecular biology of differentiated thyroid cancer for clinical prognostication

“…Unlike RET rearrangements, several authors reported a clear association of BRAF V600E with molecular features suggestive of biological and clinical aggressiveness. Particularly, the mutation was associated with decreased or absent expression of thyroid iodide-handling genes (the sodium-iodide symporter, the TSH receptor, the pendrin gene (SLC26A4), the thyroperoxidase and the thyroglobulin) (Durante et al 2007, Xing 2007, whose expression was demonstrated to be strictly dependent on that of BRAF V600E , Chakravarty et al 2011. Furthermore, BRAF mutation was associated with the overexpression of various tumour-promoting factors, such as VEGF and MET (Xing 2007).…”