Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation Journal Article
| Authors: | 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. |
| Article Title: | Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation |
| 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 (BRAFV600E) in thyroid follicular cells in a doxycycline-inducible (dox-inducible) manner. Upon dox induction of BRAFV600E, the mice developed highly penetrant and poorly differentiated thyroid tumors. Discontinuation of dox extinguished BRAFV600E expression and reestablished thyroid follicular architecture and normal thyroid histology. Switching on BRAFV600E 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 BRAFV600E 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. |
| Keywords: | controlled study; unclassified drug; gene mutation; human cell; mutation, missense; doxorubicin; nonhuman; antineoplastic agents; cell proliferation; animal cell; mouse; animals; mice; animal tissue; dna damage; apoptosis; gene expression; map kinase signaling system; mitogen activated protein kinase inhibitor; antineoplastic combined chemotherapy protocols; carcinoma, papillary; neoplasm proteins; animal experiment; animal model; enzyme activation; drug screening assays, antitumor; histology; mice, transgenic; protein kinase inhibitors; cancer inhibition; radioactive iodine; iodine radioisotopes; sulfonamides; thyroid neoplasms; hypothyroidism; thyroid gland; point mutation; indoles; doxycycline; thyroid papillary carcinoma; b raf kinase; thyroid follicle cell; map kinase kinase 1; proto-oncogene proteins b-raf; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; benzamides; diphenylamine; plx 4720; genes, synthetic; poorly differentiated thyroid cancer |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 121 |
| Issue: | 12 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2011-12-01 |
| Start Page: | 4700 |
| End Page: | 4711 |
| Language: | English |
| DOI: | 10.1172/jci46382 |
| PROVIDER: | scopus |
| PMCID: | PMC3225989 |
| PUBMED: | 22105174 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 February 2012" - "CODEN: JCINA" - "Source: Scopus" |
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