Evaluation of Tazemetostat as a Therapeutically Relevant Substance 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.

EZH2 is a key component of hepatoblastoma tumor cell growth

“…DZNep does not specifically inhibit EZH2; rather it inhibits all cellular methyltransferases which may result in off-target effects that may explain the lack of primary tumor cell response. 48 Reduced growth and morphologic changes were also observed microscopically at 72 hours post-treatment, with the greatest observed difference in GSK126-treated cells (Figure 5C). A dosedependent, reduction in growth after 24 hours was also observed at 25 and 100 μM treatments with profound cell death at 100 μM (Supporting Information Figure S4).…”

“…DZNep's mechanism of action results in increased concentration of SAH, which negatively feeds back on S‐adenosyl‐L‐methionine‐dependent histone methyltransferase. DZNep does not specifically inhibit EZH2; rather it inhibits all cellular methyltransferases which may result in off‐target effects that may explain the lack of primary tumor cell response 48 …”

“…Previous studies proposed a role for EZH2 in HB pathogenesis using the Huh6 and HepG2 cell lines. [48][49][50][51] The current study expands on these data by demonstrating that EZH2 gene and protein expression are elevated in human hepatoblastoma tumors as well as in primary tumor cell lines. Our data suggest, however, that elevated levels of EZH2 may vary from specimen to specimen.…”

The efficacy of ferroptosis-inducing compounds IKE and RSL3 correlates with the expression of ferroptotic pathway regulators CD71 and SLC7A11 in biliary tract cancer cells

“…Molecular profiling might identify patients eligible for targeted therapies (IDH1/2 mutations, FGFR 1–3 mutations and fusions, BRAF mutation, mismatch repair (MMR) deficiency, HER2 overexpression, NTRK fusions) but this applies only to selected patients [ 5 ]. Current research on BTC suggests potential alternative therapeutic approaches, including EZH2 and HDACs inhibition, but these are currently only at the preclinical stage [ 6 , 7 ]. Therefore, with the poor overall survival rate and the shortfall of effective treatment options, the discovery of novel therapeutic options against BTC is of utmost importance.…”

Editorial: Novel therapeutic approaches for biliary tract cancer and hepatocellular carcinoma

“…The incidence rates vary across geographic regions: in the Western World, the incidence ranges from 0.5 to 2 per 100,000 population, while in the Eastern World, the incidence is higher at 60 per 100,000 population (Valle et al, 2021). The molecular background of BTC development and progression is complex and remains only partially understood, although it is clear that besides mutational events and dysregulated signaling pathways, aberrant epigenetics also play a role (Mayr et al, 2015;Mayr et al, 2021;Bekric et al, 2023). Possible explanations for the low survival rates include diagnosis at an advanced stage and the development of resistance to, and ineffectiveness of current therapies as well as not standardized second-line therapies for advanced BTC (Rakic et al, 2014;Moik et al, 2019).…”