Overall, our investigations reveal a molecular dependence of ARID1A-deficient bladder cancers on PI3K/AKT signaling due to upregulation of PIK3R3 and show a synergistic antitumor activity of EZH2 and PI3K inhibitors, suggesting that this combination could be repurposed for the treatment of bladder cancer with alterations along these pathways that occur in over 40% of patients with bladder cancer. Here, EZH2 is linked to urinary bladder carcinoma.