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

Debyani Chakravarty, Elmer Santos, Mabel Ryder, Jeffrey A. Knauf, Xiao Hui Liao, Brian L. West, Gideon Bollag, Richard Kolesnick, Tin Htwe Thin, Neal Rosen, Pat Zanzonico, Steven M. Larson, Samuel Refetoff, Ronald Ghossein, James A. Fagin

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188 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4700-4711
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number12
DOIs
StatePublished - Dec 1 2011

ASJC Scopus subject areas

  • Medicine(all)

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    Chakravarty, D., Santos, E., Ryder, M., Knauf, J. A., Liao, X. H., West, B. L., Bollag, G., Kolesnick, R., Thin, T. H., Rosen, N., Zanzonico, P., Larson, S. M., Refetoff, S., Ghossein, R., & Fagin, J. A. (2011). Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. Journal of Clinical Investigation, 121(12), 4700-4711. https://doi.org/10.1172/JCI46382