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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-07-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/15/3780 |
| _version_ | 1797525700074274816 |
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| author | Vladimir Shapovalov Liliya Kopanitsa Lavinia-Lorena Pruteanu Graham Ladds David S. Bailey |
| author_facet | Vladimir Shapovalov Liliya Kopanitsa Lavinia-Lorena Pruteanu Graham Ladds David S. Bailey |
| author_sort | Vladimir Shapovalov |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T09:17:36Z |
| format | Article |
| id | doaj.art-25d60db69e2a41ec851920ce81aae61b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:17:36Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-25d60db69e2a41ec851920ce81aae61b2023-11-22T05:27:42ZengMDPI AGCancers2072-66942021-07-011315378010.3390/cancers13153780Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma CellsVladimir Shapovalov0Liliya Kopanitsa1Lavinia-Lorena Pruteanu2Graham Ladds3David S. Bailey4IOTA Pharmaceuticals Ltd., St Johns Innovation Centre, Cowley Road, Cambridge CB4 0WS, UKIOTA Pharmaceuticals Ltd., St Johns Innovation Centre, Cowley Road, Cambridge CB4 0WS, UKIOTA Pharmaceuticals Ltd., St Johns Innovation Centre, Cowley Road, Cambridge CB4 0WS, UKDepartment of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UKIOTA Pharmaceuticals Ltd., St Johns Innovation Centre, Cowley Road, Cambridge CB4 0WS, UKWe 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.https://www.mdpi.com/2072-6694/13/15/3780glioblastomadrug-inducible gene expressionMardepodectRegorafenibdrug targetstumor antigens |
| spellingShingle | Vladimir Shapovalov Liliya Kopanitsa Lavinia-Lorena Pruteanu Graham Ladds David S. Bailey Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells Cancers glioblastoma drug-inducible gene expression Mardepodect Regorafenib drug targets tumor antigens |
| title | Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells |
| title_full | Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells |
| title_fullStr | Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells |
| title_full_unstemmed | Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells |
| title_short | Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells |
| title_sort | transcriptomics based phenotypic screening supports drug discovery in human glioblastoma cells |
| topic | glioblastoma drug-inducible gene expression Mardepodect Regorafenib drug targets tumor antigens |
| url | https://www.mdpi.com/2072-6694/13/15/3780 |
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