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Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

We have used three established human glioblastoma (GBM) cell lines-U87MG, A172, and T98G-as cellular systems to examine the plasticity of the drug-induced GBM cell phenotype, focusing on two clinical drugs, the phosphodiesterase PDE10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib, using genome-wide drug-induced gene expression (DIGEX) to examine the drug response. Both drugs upregulate genes encoding specific growth factors, transcription factors, cellular signaling molecules, and cell surface proteins, while downregulating a broad range of targetable cell cycle and apoptosis-associated genes. A few upregulated genes encode therapeutic targets already addressed by FDA approved drugs, but the majority encode targets for which there are no approved drugs. Amongst the latter, we identify many novel druggable targets that could qualify for chemistry-led drug discovery campaigns. We also observe several highly upregulated transmembrane proteins suitable for combined drug, immunotherapy, and RNA vaccine approaches. DIGEX is a powerful way of visualizing the complex drug response networks emerging during GBM drug treatment, defining a phenotypic landscape which offers many new diagnostic and therapeutic opportunities. Nevertheless, the extreme heterogeneity we observe within drug-treated cells using this technique suggests that effective pan-GBM drug treatment will remain a significant challenge for many years to come.

 

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The study examined the plasticity of drug-induced phenotypes in three human glioblastoma cell lines using two clinical drugs, Mardepodect and Regorafenib. The researchers used genome-wide drug-induced gene expression (DIGEX) analysis to identify the drugs' effects on gene expression. The results showed that both drugs upregulated genes encoding specific growth factors, transcription factors, cellular signaling molecules, and cell surface proteins, while downregulating cell cycle and apoptosis-associated genes that could be targeted by drugs.

While some of the upregulated genes encode therapeutic targets that have already been addressed by FDA-approved drugs, the majority of genes encode targets for which there are no approved drugs. The study identifies many novel druggable targets that could be pursued through chemistry-led drug discovery campaigns. Additionally, the study identifies several highly upregulated transmembrane proteins that could be targeted through combined drug, immunotherapy, and RNA vaccine approaches.

The results of the study offer new diagnostic and therapeutic opportunities for GBM treatment. However, the extreme heterogeneity observed within drug-treated cells using DIGEX suggests that effective pan-GBM drug treatment will remain a significant challenge for many years to come.

Related Products

Cat.No. Product Name Information
S2687 Mardepodect (PF-2545920) Mardepodect (PF-2545920) is a potent and selective PDE10A inhibitor with IC50 of 0.37 nM, with >1000-fold selectivity over the PDE.

Related Targets

PDE