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Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells
PURPOSE: We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232604/ https://www.ncbi.nlm.nih.gov/pubmed/37183219 http://dx.doi.org/10.1007/s11060-023-04319-1 |
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author | Valinciute, Gintvile Ecker, Jonas Selt, Florian Hielscher, Thomas Sigaud, Romain Ridinger, Johannes Thatikonda, Venu Gatzweiler, Charlotte Robinson, Sarah Talbot, Julie Bernardi, Flavia Picard, Daniel Blattner-Johnson, Mirjam Schmid, Simone Jones, David T. van Tilburg, Cornelis M. Capper, David Kool, Marcel Remke, Marc Oehme, Ina Pfister, Stefan M. Roussel, Martine F. Ayrault, Olivier Witt, Olaf Milde, Till |
author_facet | Valinciute, Gintvile Ecker, Jonas Selt, Florian Hielscher, Thomas Sigaud, Romain Ridinger, Johannes Thatikonda, Venu Gatzweiler, Charlotte Robinson, Sarah Talbot, Julie Bernardi, Flavia Picard, Daniel Blattner-Johnson, Mirjam Schmid, Simone Jones, David T. van Tilburg, Cornelis M. Capper, David Kool, Marcel Remke, Marc Oehme, Ina Pfister, Stefan M. Roussel, Martine F. Ayrault, Olivier Witt, Olaf Milde, Till |
author_sort | Valinciute, Gintvile |
collection | PubMed |
description | PURPOSE: We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy. METHODS: We used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou–Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment. RESULTS: MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination. CONCLUSION: The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood–brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-023-04319-1. |
format | Online Article Text |
id | pubmed-10232604 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-102326042023-06-02 Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells Valinciute, Gintvile Ecker, Jonas Selt, Florian Hielscher, Thomas Sigaud, Romain Ridinger, Johannes Thatikonda, Venu Gatzweiler, Charlotte Robinson, Sarah Talbot, Julie Bernardi, Flavia Picard, Daniel Blattner-Johnson, Mirjam Schmid, Simone Jones, David T. van Tilburg, Cornelis M. Capper, David Kool, Marcel Remke, Marc Oehme, Ina Pfister, Stefan M. Roussel, Martine F. Ayrault, Olivier Witt, Olaf Milde, Till J Neurooncol Research PURPOSE: We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy. METHODS: We used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou–Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment. RESULTS: MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination. CONCLUSION: The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood–brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-023-04319-1. Springer US 2023-05-15 2023 /pmc/articles/PMC10232604/ /pubmed/37183219 http://dx.doi.org/10.1007/s11060-023-04319-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Valinciute, Gintvile Ecker, Jonas Selt, Florian Hielscher, Thomas Sigaud, Romain Ridinger, Johannes Thatikonda, Venu Gatzweiler, Charlotte Robinson, Sarah Talbot, Julie Bernardi, Flavia Picard, Daniel Blattner-Johnson, Mirjam Schmid, Simone Jones, David T. van Tilburg, Cornelis M. Capper, David Kool, Marcel Remke, Marc Oehme, Ina Pfister, Stefan M. Roussel, Martine F. Ayrault, Olivier Witt, Olaf Milde, Till Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells |
title | Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells |
title_full | Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells |
title_fullStr | Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells |
title_full_unstemmed | Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells |
title_short | Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells |
title_sort | class i hdac inhibitor entinostat synergizes with plk1 inhibitors in myc-amplified medulloblastoma cells |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10232604/ https://www.ncbi.nlm.nih.gov/pubmed/37183219 http://dx.doi.org/10.1007/s11060-023-04319-1 |
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