An Integrated Strategy for Predicting Cancer Aggressiveness and Therapeutic Vulnerability in Muscle Invasive Bladder Cancer

Despite advances in molecular characterization and drug development, identifying predictive biomarkers with therapeutic potentials remains challenging in the management of muscle-invasive bladder cancer (MIBC). To address this, we applied high-dimensional regression analysis using the HDMAC platform to overexpressed genes in MIBC which associated with poor overall survivals. A unique six-gene panel (ARID3A, ARMH4, P4HB, PPT2, PRPF19, and SLC1A6) was defined exhibiting additive prognostic value for determining MIBC aggressiveness. This panel was cross-validated in independent cohorts using a generalized additive model, and its transcriptomic profiles were linked to neuronal and luminal molecular subtypes. Among these genes, PPT2 and PRPF19 were identified as novel, druggable targets which showed gene-dependent cell vulnerabilities. PPT2 participates in lysosome/autophagy-mediated protein degradation, whereas PRPF19 serves as a central hub connecting the spliceosome, DNA replication machinery, and proteasome. Using PRISM drug bank data, potential lead compounds were identified through mechanism-of-action matching: anchusin and patupilone (targeting PPT2), and selumetinib and STA-5326 (targeting PRPF19). This integrated approach revealed PPT2 and PRPF19 as actionable predictive biomarkers for aggressive MIBC and suggests that protein degradation mediated by autophagosome/lysosome or proteasome pathways plays a critical role in MIBC progression.