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

TLDR

Advanced human thyroid cancers, especially those refractory to radioiodine, frequently harbor BRAF mutations, yet the degree of their dependence on BRAF expression remains unclear. The study aimed to determine how dependent thyroid cancers are on BRAF expression. The authors created a doxycycline‑inducible mouse model expressing BRAF(V600E) in thyroid follicular cells. Induction of BRAF(V600E) produced aggressive, poorly differentiated tumors that lost thyroid function and radioiodine uptake, all of which were reversed by doxycycline withdrawal; pharmacologic inhibition of MEK or mutant BRAF reduced proliferation, partially restored thyroid gene expression, and restored radioiodine sensitivity, showing that BRAF(V600E)–driven tumors depend on the oncoprotein for viability and radioiodine uptake.

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.