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

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 Braf(V600E) 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.

• Authors: David G McFadden, Amanda Vernon, Philip M Santiago, Raul Martinez-McFaline, Arjun Bhutkar, Denise M Crowley, Martin McMahon, Peter M Sadow, Tyler Jacks
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 16 Pg. E1600-9 (Apr 22 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24711431 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Tumor Suppressor Protein p53
• Thyrotropin
• Braf protein, mouse
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Carcinoma (blood, drug therapy, genetics, pathology)
• Carcinoma, Papillary
• Cell Differentiation (drug effects, genetics)
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Disease Progression
• Gene Expression Regulation, Neoplastic (drug effects)
• Homozygote
• Humans
• MAP Kinase Signaling System (drug effects, genetics)
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Mutation (genetics)
• Neoplasm Grading
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
• Thyroid Cancer, Papillary
• Thyroid Carcinoma, Anaplastic
• Thyroid Gland (drug effects, pathology)
• Thyroid Neoplasms (blood, drug therapy, genetics, pathology)
• Thyrotropin (blood)
• Tumor Suppressor Protein p53 (metabolism)