Consistent with the observation that the activation of EZH2 mediated resistance to PI3Kα inhibitors in ESCC cells, simultaneously targeting EZH2 significantly improved the efficacy of CYH33 against ESCC cells and ESCC PDXs, accompanied by reduced RB phosphorylation and enhanced G1 phase arrest. This evidence concerns the gene EZH2 and esophageal squamous cell carcinoma.