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

Overview

MeSH Major

  • Antineoplastic Agents
  • Carcinoma, Papillary
  • Indoles
  • Iodine Radioisotopes
  • MAP Kinase Signaling System
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • Sulfonamides
  • Thyroid Neoplasms

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.

publication date

  • December 2011

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3225989

Digital Object Identifier (DOI)

  • 10.1172/JCI46382

PubMed ID

  • 22105174

Additional Document Info

start page

  • 4700

end page

  • 11

volume

  • 121

number

  • 12