TRβ Agonism Induces Tumor Suppression and Enhances Drug Efficacy in Anaplastic Thyroid Cancer in Female Mice

Abstract

Background: Anaplastic thyroid cancer (ATC) is one of the most lethal endocrine cancers, with an average survival time of six months after diagnosis. These aggressive tumors have very limited treatment options highlighting a need for a deeper understanding of its mechanisms for development of more effective therapies. We have previously shown that the liganded thyroid hormone receptor beta (TRβ) can function as a tumor suppressor and induce re-differentiation in ATC cells. We therefore tested the hypothesis that selective activation of TRβ with sobetirome (GC-1) could reduce the tumorigenic phenotypes of ATC cell lines and improve the efficacy of clinically relevant therapeutics. Methods: We used a panel of four ATC cell lines with variable genetic backgrounds to assess the ability of GC-1 to reduce the aggressive phenotype. The effects of GC-1 alone or in combination with buparlisib, alpelisib, sorafenib, and palbociclib on cell growth, viability, and migration were determined and compared with the gene expression levels of selected markers. The impact of these treatments on the cancer stem cell population was assessed by tumorsphere assay. Thyroid differentiation markers were measured by gene analysis, and sodium iodide symporter (NIS) protein level and function were determined. Results: Our results show that GC-1 alone can decrease cell viability, growth, and slow cell migration in all four ATC cell lines. In addition, GC-1 is able to further block each of these phenotypes when combined with buparlisib, alpelisib, sorafenib, or palbociclib. GC-1 alone blocks thyrosphere outgrowth in all cell lines and increases the efficacy of each of the therapeutic agents tested. GC-1 increased NIS transcript and protein levels to allow for increased iodide uptake in ATC cells. Conclusion: Activation of TRβ with selective agonist sobetirome (GC-1) reduces the aggressive phenotype and induced re-differentiation in ATC cells and increases the efficacy of therapeutic agents that are currently used in the treatment of ATC. These results indicate that selective activation of TRβ not only induces a tumor suppression program de novo but enhances the effectiveness of anti-cancer agents.