p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer

David G. McFadden, Amanda Vernon, Philip M. Santiago, Raul Martinez-McFaline, Arjun Bhutkar, Denise M. Crowley, Martin McMahon, Peter M. Sadow, and Tyler Jacks
PNAS published ahead of print April 7, 2014 https://doi.org/10.1073/pnas.1404357111

  1. Contributed by Tyler Jacks, March 18, 2014 (sent for review December 12, 2013)

Significance

We generated a thyroid-specific CreER transgenic mouse and used this strain to model progression of v-raf murine sarcoma viral oncogene homolog B (BRAF)-mutant papillary thyroid cancer to anaplastic thyroid cancer (ATC). These murine tumors recapitulated the temporal progression and molecular hallmarks of human ATC. We demonstrated that combined mapk/Erk kinase (MEK) and BRAF inhibition resulted in enhanced antitumor activity vs. single-agent BRAF inhibitors in this preclinical model. This model represents a previously lacking mouse model of BRAF-mutant ATC and adds to the experimental armamentarium of a highly lethal disease in need of scientific advances. These data also suggest that potent inhibition of the MAPK pathway may improve outcomes in advanced thyroid cancers.

Abstract

Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated BrafV600E mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: tjacks{at}mit.edu.

  • Author contributions: D.G.M. and T.J. designed research; D.G.M., A.V., P. M. Santiago, R.M.-M., and D.M.C. performed research; M.M. contributed new reagents/analytic tools; D.G.M., A.B., and P. M. Sadow analyzed data; and D.G.M. wrote the paper.

  • The authors declare no conflict of interest.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE55933).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1404357111/-/DCSupplemental.

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Mouse model of anaplastic thyroid cancer
David G. McFadden, Amanda Vernon, Philip M. Santiago, Raul Martinez-McFaline, Arjun Bhutkar, Denise M. Crowley, Martin McMahon, Peter M. Sadow, Tyler Jacks
Proceedings of the National Academy of Sciences Apr 2014, 201404357; DOI: 10.1073/pnas.1404357111
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