A Thyroid Hormone Receptor Beta Specific Agonist Suppresses Anaplastic Thyroid Cancer Cell Phenotype and Increases Efficacy of Therapeutic Agents
Gillis, N. E.; Davidson, C. D.; Cozzens, L. M.; Wilson, E. R.; Bolf, E. L.; Tomczak, J. A.; Carr, F. E.
Show abstract
Thyroid hormone receptor beta (TR{beta}) is a recognized tumor suppressor in numerous solid cancers. The molecular signaling of TR{beta} has been elucidated in several cancer types through re-expression models. Remarkably, the potential impact of selective activation of endogenous TR{beta} on tumor progression remains largely unexplored. We used cell-based and in vivo assays to evaluate the effects of the TR{beta} agonist Sobetirome (GC-1) on a particularly aggressive and dedifferentiated cancer, anaplastic thyroid cancer (ATC). Here we report that GC-1 reduced the tumorigenic phenotype, decreased cancer stem-like cell populations, and induced re-differentiation of the ATC cell lines with different mutational backgrounds. Of note, this selective activation of TR{beta} amplified the effects of therapeutic agents in blunting the aggressive cell phenotype and stem-cell growth. In xenograft assays, GC-1 alone inhibited tumor growth and was as effective as the kinase inhibitor, Sorafenib. These results indicate that selective activation of TR{beta} not only induces a tumor suppression program de novo but enhances the effectiveness of anti-cancer agents revealing potential novel combination therapies for ATC and other aggressive solid tumors.
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