AP1M2 Drives Gemcitabine‐Cisplatin Chemoresistance by Enhancing RAD54B‐Associated DNA Repair in Bladder Cancer

ABSTRACT The combination of gemcitabine and cisplatin serves as a cornerstone in bladder cancer (BC) treatment, yet chemotherapy resistance continues to pose a significant challenge. This study utilizes a novel BC organoid model integrated with drug sensitivity assays to uncover the mechanisms underlying resistance and identify potential therapeutic targets. Our findings reveal that AP1M2 expression is markedly upregulated in gemcitabine‐ and cisplatin‐resistant BC cells and tissues. Elevated AP1M2 levels contribute to enhanced chemotherapy resistance and tumor cell proliferation by facilitating the DNA damage response and increasing RAD54B expression. Mechanistically, AP1M2 interacts with the RNA‐binding protein PUM1 to stabilize RAD54B mRNA, thereby supporting DNA repair and survival under chemotherapeutic stress. Notably, inhibition of AP1M2/PUM1‐mediated RAD54B expression sensitized BC xenografts to gemcitabine‐cisplatin treatment in vivo. These findings unveil a novel mechanism of chemotherapy resistance in BC and highlight the AP1M2/PUM1/RAD54B pathway as a promising therapeutic target to counter resistance and enhance treatment outcomes.