Ezh2 Inhibition by Tazemetostat: Mechanisms of Action, Safety and Efficacy in Relapsed/refractory Follicular Lymphoma

Epigenetic alterations are major drivers of follicular lymphomagenesis, and these alterations are frequently caused by mutations in or upregulation of <i>EZH2</i>, a histone methyltransferase responsible for PRC2-mediated gene repression. EZH2 hyperactivation increases proliferation of B cells and prevents them from exiting the germinal center, favoring lymphomagenesis. The first FDA-approved EZH2 inhibitor is tazemetostat, which is orally available and targets both mutant and wild-type forms of the protein to induce cell cycle arrest and apoptosis of lymphoma cells in preclinical models. Phase II trials have shown objective response rates of 69% for patients with lymphoma-carrying <i>EZH2</i> mutations and 35% for those with wild-type <i>EZH2</i> without major toxicity, leading to tazemetostat approval for this cancer by the US FDA in June 2020.