EZH2 Inhibition Remodels Cell States and Enhances EGFRi Sensitization in Bladder Cancer

Area of Science:

• Oncology
• Epigenetics
• Genomics

Background:

• Bladder cancer (BCa) exhibits significant interpatient heterogeneity and epigenetic plasticity, potentially hindering treatment effectiveness.
• Understanding the role of Enhancer of zeste homolog 2 (EZH2) in modulating tumor cell states is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate if EZH2 inhibition can remodel tumor cell states and create therapeutic vulnerabilities in bladder cancer.
• To assess the potential of combining EZH2 inhibition with epidermal growth factor receptor (EGFR)-targeted therapy.

Main Methods:

• Integrated single-nucleus RNA sequencing (snRNA-seq) of primary tumors with single-cell RNA sequencing (scRNA-seq) of matched patient-derived organoids (PDOs).
• Treatment of PDOs with the EZH2 inhibitor tazemetostat, followed by sequential afatinib (EGFR inhibitor) treatment.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to analyze epigenomic changes (H3K27me3 and EZH2 occupancy) and gene set enrichment analysis (GSEA) for pathway alterations.

Main Results:

• PDOs selectively retained and expanded tumor-intrinsic stress- and plasticity-associated epithelial states compared to native tumors.
• EZH2 inhibition induced heterogeneous reprogramming, including inflammatory, proliferative, hypoxic/glycolytic, and neural/neuroendocrine (NE)-like programs.
• Downregulation of EGFR tyrosine kinase inhibitor resistance signatures and enhanced afatinib sensitivity were observed after sequential tazemetostat and afatinib treatment.

Conclusions:

• EZH2 acts as a context-dependent regulator of cell-state plasticity in bladder cancer.
• While EZH2 inhibition alone leads to heterogeneous adaptive responses, it suppresses resistance pathways to EGFR inhibitors.
• Sequential epigenetic priming with EZH2 inhibitors followed by EGFR-targeted therapy warrants further investigation in BCa treatment.