High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes

by Selleckchem | Jun 14 2023

Molecular subtypes of muscle-invasive bladder cancer (MIBC) display differential survival and drug sensitivities in clinical trials. To date, they have not been used as a paradigm for phenotypic drug discovery. This study aimed to discover novel subtype-stratified therapy approaches based on high-content screening (HCS) drug discovery. Transcriptome expression data of CCLE and BLA-40 cell lines were used for molecular subtype assignment in basal, luminal, and mesenchymal-like cell lines. Two independent HCSs, using focused compound libraries, were conducted to identify subtype-specific drug leads. We correlated lead drug sensitivity data with functional genomics, regulon analysis, and in-vitro drug response-based enrichment analysis. The basal MIBC subtype displayed sensitivity to HDAC and CHK inhibitors, while the luminal subtype was sensitive to MDM2 inhibitors. The mesenchymal-like cell lines were exclusively sensitive to the ITGAV inhibitor SB273005. The role of integrins within this mesenchymal-like MIBC subtype was confirmed via its regulon activity and gene essentiality based on CRISPR-Cas9 knock-out data. Patients with high ITGAV expression showed a significant decrease in the median overall survival. Phenotypic high-content drug screens based on bladder cancer cell lines provide rationales for novel stratified therapeutic approaches as a framework for further prospective validation in clinical trials.

Comments:

The study aimed to explore novel therapeutic approaches for muscle-invasive bladder cancer (MIBC) based on the molecular subtypes of the disease. The researchers utilized high-content screening (HCS) drug discovery to identify subtype-specific drug leads.

To assign molecular subtypes, transcriptome expression data from CCLE and BLA-40 cell lines were analyzed, categorizing them into basal, luminal, and mesenchymal-like subtypes. Subsequently, two independent HCS experiments were conducted using focused compound libraries to identify drugs that showed efficacy against specific subtypes.

The findings revealed differential drug sensitivities among the subtypes. The basal subtype of MIBC displayed sensitivity to HDAC (histone deacetylase) and CHK (checkpoint kinase) inhibitors. In contrast, the luminal subtype exhibited sensitivity to MDM2 inhibitors. The mesenchymal-like cell lines were specifically sensitive to an ITGAV inhibitor called SB273005.

To further understand the underlying mechanisms, the researchers correlated the drug sensitivity data with functional genomics, regulon analysis, and in-vitro drug response-based enrichment analysis. They confirmed the involvement of integrins within the mesenchymal-like MIBC subtype by studying its regulon activity and gene essentiality based on CRISPR-Cas9 knock-out data.

Importantly, high expression of ITGAV was associated with a significant decrease in median overall survival in patients. This highlights the clinical relevance of the findings and suggests the potential for using ITGAV inhibitors as a targeted therapy for patients with mesenchymal-like MIBC.

The study demonstrates the potential of using high-content drug screens based on bladder cancer cell lines to identify subtype-specific therapies. These findings provide a foundation for developing novel stratified therapeutic approaches, which could be further validated in prospective clinical trials.