High-Content Drug Discovery Targeting Molecular Bladder Cancer Subtypes

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-co...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-09, Vol.23 (18), p.10605
Main Authors: Rinaldetti, Sébastien, Zhou, Qiong, Abbott, Joshua M., de Jong, Florus C., Esquer, Hector, Costello, James C., Theodorescu, Dan, LaBarbera, Daniel V.
Format: Article
Language:English
Subjects:
Biomarkers
Bladder cancer
Cancer
Cancer therapies
Cell cycle
Clinical trials
CRISPR
Drug discovery
Drug screening
Drugs
Gene expression
Genotype & phenotype
Histone deacetylase
Inhibitors
Integrins
Invasiveness
Kinases
MDM2 protein
Mesenchyme
Methyl isobutyl carbinol
molecular subtype
Muscles
Smooth muscle
Survival
Taxonomy
Transcriptomes
Tumor cell lines
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms231810605