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 types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / toxicity
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Apoptosis / drug effects
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Benzamides / administration & dosage
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Benzamides / pharmacology
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Benzamides / therapeutic use
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Benzamides / toxicity
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Carcinoma, Papillary / drug therapy*
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Carcinoma, Papillary / genetics
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Carcinoma, Papillary / metabolism
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Carcinoma, Papillary / pathology
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DNA Damage
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Diphenylamine / administration & dosage
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Diphenylamine / analogs & derivatives
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Diphenylamine / pharmacology
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Diphenylamine / therapeutic use
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Diphenylamine / toxicity
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Doxorubicin / pharmacology
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Drug Screening Assays, Antitumor
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Enzyme Activation / drug effects
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Genes, Synthetic / drug effects
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Humans
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Indoles / administration & dosage
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Indoles / pharmacology
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Indoles / therapeutic use*
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Indoles / toxicity
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Iodine Radioisotopes / pharmacokinetics*
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / physiology
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Mice
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Mice, Transgenic
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Mutation, Missense
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Point Mutation
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Protein Kinase Inhibitors / toxicity
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / physiology*
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use*
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Sulfonamides / toxicity
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Thyroid Gland / metabolism
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Thyroid Neoplasms / drug therapy*
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / metabolism
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Thyroid Neoplasms / pathology
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Vemurafenib
Substances
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Antineoplastic Agents
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Benzamides
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Indoles
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Iodine Radioisotopes
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Sulfonamides
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Vemurafenib
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Doxorubicin
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mirdametinib
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Diphenylamine
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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MAP Kinase Kinase 1