Evaluation of Tazemetostat as a Therapeutically Relevant Substance in Biliary Tract Cancer

SIMPLE SUMMARY: Treating biliary tract cancer (BTC) successfully remains to be a difficult task. Standard therapeutic options encompass surgery, radiation and chemotherapy, but the median survival has not improved beyond one year. The reasons for this might be diagnosis at an already late stage and resistance towards current therapy. Therefore, novel strategies to combat this gastrointestinal disease need to be investigated. One alternative option may be to inhibit the enhancer of Zeste homolog 2 (EZH2), a histone-lysine-N-methyltransferase that was already shown to play a role in oncogenesis in BTC. Tazemetostat, an FDA-approved EZH2-inhibitor, seems to harbor promising anti-cancer properties in various tumor types. Therefore, in this study, we aim to investigate for the first time if tazemetostat might be a potential novel therapeutic strategy in biliary tract cancer. ABSTRACT: Biliary tract cancer (BTC) is a gastrointestinal malignancy associated with a poor survival rate. Current therapies encompass palliative and chemotherapeutic treatment as well as radiation therapy, which results in a median survival of only one year due to standard therapeutic ineffectiveness or resistance. Tazemetostat is an FDA-approved inhibitor of enhancer of Zeste homolog 2 (EZH2), a methyltransferase involved in BTC tumorigenesis via trimethylation of histone 3 at lysine 27 (H3K27me3), an epigenetic mark associated with silencing of tumor suppressor genes. Up to now, there are no data available regarding tazemetostat as a possible treatment option against BTC. Therefore, the aim of our study is a first-time investigation of tazemetostat as a potential anti-BTC substance in vitro. In this study, we demonstrate that tazemetostat affects cell viability and the clonogenic growth of BTC cells in a cell line-dependent manner. Furthermore, we found a strong epigenetic effect at low concentrations of tazemetostat, which was independent of the cytotoxic effect. We also observed in one BTC cell line that tazemetostat increases the mRNA levels and protein expression of the tumor suppressor gene Fructose-1,6-bisphosphatase 1 (FBP1). Interestingly, the observed cytotoxic and epigenetic effects were independent of the mutation status of EZH2. To conclude, our study shows that tazemetostat is a potential anti-tumorigenic substance in BTC with a strong epigenetic effect.