BACE2 Promotes Bladder Cancer Chemoresistance Through Proteolytic Activation of JAG1-Notch Signaling.

Background: Chemoresistance to platinum-based regimens, primarily gemcitabine plus cisplatin, remains a major obstacle in the treatment of advanced bladder cancer. Identifying the underlying molecular mechanisms is critical for developing effective therapeutic strategies to improve clinical outcomes. Methods: Integrative analysis of transcriptomic profiles from chemoresistant bladder cancer models and clinical data sets from The Cancer Genome Atlas was performed to identify candidate resistance drivers. The biological function of the candidate gene was evaluated in vitro using bladder cancer cell lines. Mechanistic investigations, including transcriptomic analyses and immunoprecipitation, were conducted to elucidate downstream signaling. The therapeutic potential of targeting this axis was assessed in vitro and in an in vivo xenograft model using a small-molecule inhibitor combined with chemotherapy. Results: We identified β-secretase 2 (BACE2) as a candidate mediator of cisplatin resistance. Conclusions: These results define a novel BACE2-JAG1-Notch signaling axis that contributes to bladder cancer chemoresistance. Importantly, our findings identify BACE2 as a potential prognostic biomarker and a therapeutically actionable target to improve clinical outcomes in this disease.