Abstract 2464: Novel mechanism driving p53 loss that dictates bladder cancer aggressive phenotypes

Abstract Bladder cancer (BLCA) remains a clinically heterogeneous disease, characterized by high mutational burden, recurrence rates, and poor survival in advanced stages. Identifying molecular drivers of progression and therapy resistance is crucial for improving patient outcomes. In muscle-invasive bladder cancer (MIBC), loss of p53 is a major molecular hallmark that drives aggressive basal/squamous-like subtypes, conferring resistance to cell killing and immune evasion. However, the mechanisms underlying p53 inactivation/loss remain thus far unrealized. We previously showed that Retinal Degeneration Protein 3 (RD3) is widely expressed in the body and plays a tumor-protective role. In this study, we investigated the clinical significance of RD3 loss and its interplay with p53 status in a cohort of 107 BLCA patients. Using a custom-archived tissue microarray, RD3 expression was profiled (immunohistochemistry). We observed a complete loss of RD3 in aggressive BLCA tumors when compared with clinically favorable non-muscle invasive bladder cancer (NMIBC). RD3 loss strongly correlated with advanced tumor stage (MIBC), disease dissemination, therapy resistance, metastasis, and recurrence. Survival analysis indicated a strong trend toward decreased overall survival (OS), progression-free survival (PFS), and relapse-free survival (RFS) in RD3-deficient cases. In parallel, p53 expression in the same cohort demonstrated similar associations, confirming that compromised p53 is a defining feature of advanced BLCA. More importantly, our findings indicate a linear association of RD3 loss with p53 loss. Owing to the upstream effector function of RD3 regulating p53 competitor NFκB, the findings throw light on the RD3→p53 signaling flow-through in BLCA evolution. This dual loss could represent a synergistic axis driving disease progression and therapeutic failure in BLCA. These results position RD3 as a potential prognostic biomarker and therapeutic target, especially in p53-deficient tumors. The current focus of our studies are in the line of delineating the RD3-p53 regulatory network and its implications for precision medicine for high-risk BLCA patients. Funding: DoD CA-210339; OCAST-HR19-045; P20GM103639 Citation Format: Sabir Salim, Sreenidhi Mohanvelu, Poorvi Subramanian, Afsana Parveen Jahir Hussain, Sheeja Aravindan, Natarajan Aravindan. Novel mechanism driving p53 loss that dictates bladder cancer aggressive phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2464.