Proteomic profiling identifies muscle-invasive bladder cancers with distinct biology and responses to platinum-based chemotherapy

Abstract Platinum-based neoadjuvant chemotherapy (NAC) prior to radical cystectomy is the preferred treatment for muscle-invasive bladder cancer (MIBC) despite modest survival benefit and significant associated toxicities. Here, we profiled the global proteome of MIBC tumours pre- and post-NAC treatment using archival formalin-fixed paraffin-embedded tissue. We identified four pre-NAC proteomic clusters with distinct biology and response to therapy and integrated these with transcriptomic subtypes and immunohistochemistry. We observed proteomic plasticity post-NAC that was associated with increased extracellular matrix and reduced keratinization compared to pre-NAC. Post-NAC clusters appeared to be differentially enriched for druggable proteins. For example, MTOR and PARP were over-expressed at the protein level in tumours identified as neuronal-like. In addition, we determined that high intratumoural proteome heterogeneity in pre-NAC tissue was associated with worse prognosis. Our work highlights new aspects of MIBC tumour biology associated with clinical outcomes, and suggests new biomarkers and therapeutic targets based on proteomic clusters.