In this study, we show that ABT-263 in combination with 5-FU strongly induces apoptosis and enhances sensitivity to both EAC as well as ESCC; most importantly the combination is lethal to chemo-resistant cells by targeting CSCs population through inhibiting Wnt/β-catenin and or YAP-1/SOX9 axes. This evidence concerns the gene SOX9 and esophageal squamous cell carcinoma.