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

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 overlaid 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 intra-tumour 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 therapeutic targets based on proteomic clusters.