TR[beta] Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice

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 redifferentiation 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 anticancer agents, revealing potential novel combination therapies for ATC and other aggressive solid tumors. Key Words: GC-1, sobetirome, thyroid hormone receptor, anaplastic thyroid cancer Abbreviations: ANOVA, analysis of variance; ATC, anaplastic thyroid cancer; BSA, bovine serum albumin; DAPI, 4',6-diamidino-2-phenylindole; GC-1, sobetirome; MAPK, mitogen-activated protein kinase; PBS, phosphate-buffered saline; PI3K, phosphatidylinositol 3-kinase; qRT-PCR, quantitative real-time polymerase chain reaction; [T.sub.3], triiodothyronine; TR[beta], thyroid hormone receptor beta.