Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine Academic Article uri icon

Overview

MeSH Major

  • Benzimidazoles
  • Extracellular Signal-Regulated MAP Kinases
  • Iodine Radioisotopes
  • MAP Kinase Signaling System
  • Mutation, Missense
  • Proto-Oncogene Proteins B-raf
  • Thyroid Neoplasms

abstract

  • Radioiodide (RAI) therapy of thyroid cancer exploits the relatively selective ability of thyroid cells to transport and accumulate iodide. Iodide uptake requires expression of critical genes that are involved in various steps of thyroid hormone biosynthesis. ERK signaling, which is markedly increased in thyroid cancer cells driven by oncogenic BRAF, represses the genetic program that enables iodide transport. Here, we determined that a critical threshold for inhibition of MAPK signaling is required to optimally restore expression of thyroid differentiation genes in thyroid cells and in mice with BrafV600E-induced thyroid cancer. Although the MEK inhibitor selumetinib transiently inhibited ERK signaling, which subsequently rebounded, the MEK inhibitor CKI suppressed ERK signaling in a sustained manner by preventing RAF reactivation. A small increase in ERK inhibition markedly increased the expression of thyroid differentiation genes, increased iodide accumulation in cancer cells, and thereby improved responses to RAI therapy. Only a short exposure to the drug was necessary to obtain a maximal response to RAI. These data suggest that potent inhibition of ERK signaling is required to adequately induce iodide uptake and indicate that this is a promising strategy for the treatment of BRAF-mutant thyroid cancer.

publication date

  • November 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5096947

Digital Object Identifier (DOI)

  • 10.1172/JCI89067

PubMed ID

  • 27669459

Additional Document Info

start page

  • 4119

end page

  • 4124

volume

  • 126

number

  • 11