Role of androgen receptor signaling in chemoresistance in urothelial cancer: a narrative review.

BACKGROUND AND

OBJECTIVE

Intravesical instillation of chemotherapeutic drugs remains a cornerstone in the management of non-muscle-invasive bladder tumor following transurethral surgery, where they are routinely employed to prevent disease recurrence and progression. In patients with locally advanced or metastatic urothelial carcinoma, cisplatin-based combination chemotherapy continues to represent the standard systemic treatment and has also been used in the neoadjuvant setting prior to radical cystectomy. Despite these established strategies, a substantial proportion of these patients exhibit intrinsic or acquired resistance to chemotherapeutic regimens, ultimately leading to poor oncologic outcomes, although the molecular mechanisms underlying chemoresistance remain only partially understood. Meanwhile, accumulating evidence has increasingly suggested a critical role of androgen receptor (AR) signaling in promoting not only the development and progression of urothelial cancer but also resistance to conventional non-surgical therapy for bladder cancer. In this review article, we aim to summarize available data suggesting that AR is involved in chemosensitivity in urothelial cancer.

METHODS

We searched five scholarly databases [PubMed, Embase, Scopus, Google Scholar, and World Health Organization (WHO) Global Index Medicus], using the relevant keywords variably combined. Studies published in English from January 1950 to January 2026 were considered.

KEY CONTENT AND FINDINGS: This article focuses on synthesizing current knowledge regarding the involvement of AR in modulating the efficacy of chemotherapeutic agents used for bladder cancer and discusses their potential of overcoming chemoresistance. Several potential downstream effectors of AR signaling, which increase or decrease chemosensitivity, have also been identified.

CONCLUSIONS

Available data may indicate that therapeutic strategies incorporating anti-AR therapy, apart from its direct anti-tumor activity, may hold considerable promise as a sensitizer of chemotherapy in patients with urothelial cancer.