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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
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.
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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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