Simplified Molecular Classification of Urothelial Carcinoma via Multi-Omic Profiling: Implications for Precision Therapy

High-risk stroma-rich cluster #1 cancers were predicted to respond to selected cytotoxic drugs, ferroptosis inducers, and PARP inhibitors. For the aggressive, fast proliferating and immune-infiltrated cluster #2 tumors with basal/squamous differentiation, cytotoxic agents and EGFR/ERBB- and MEK/ERK-targeting therapy was proposed. Cluster #3 cancers of predominantly luminal papillary phenotype, with scarce stroma and immune infiltration were enriched with NMIBC and low-risk malignancies.

For cluster #3 patients, selected epigenetic drugs or EGFR/FGFR inhibitors may pose an attractive treatment option. This molecular taxonomy holds promise as a practical framework for patient stratification and therapeutic guidance in UC. Our molecular classification scheme may facilitate personalized transcriptome- and proteome-based risk assessment and therapy guidance, and the development of new cancer medication.