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000276078 1001_ $$0P:(DE-He78)40aa4331020bebaf3e1801700d2d3267$$aValinciute, Gintvile$$b0$$eFirst author
000276078 245__ $$aClass I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells.
000276078 260__ $$aDordrecht [u.a.]$$bSpringer Science + Business Media B.V$$c2023
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000276078 500__ $$a#EA:B310#LA:B310# / 2023 May;163(1):143-158
000276078 520__ $$aWe 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.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.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.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.
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000276078 650_7 $$2Other$$aHDAC inhibitor
000276078 650_7 $$2Other$$aMYC
000276078 650_7 $$2Other$$aMedulloblastoma
000276078 650_7 $$2Other$$aPLK1 inhibitor
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000276078 7001_ $$aRobinson, Sarah$$b8
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000276078 7001_ $$aBernardi, Flavia$$b10
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000276078 7001_ $$aRoussel, Martine F$$b21
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000276078 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b24$$eLast author$$udkfz
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