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000181244 1001_ $$0P:(DE-He78)a23e88cc676489fe05be8c178ceaf58e$$aSelt, Florian$$b0$$eFirst author$$udkfz
000181244 245__ $$aBH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.
000181244 260__ $$aOxford$$bOxford Univ. Press$$c2023
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000181244 500__ $$a#EA:B310#LA:B310# / 2023 Apr 6;25(4):735-747
000181244 520__ $$aPilocytic astrocytoma (PA) is the most common pediatric brain tumor and a mitogen-activated protein kinase (MAPK)-driven disease. Oncogenic MAPK-signaling drives the majority of cells into oncogene-induced senescence (OIS). While OIS induces resistance to anti-proliferative therapies, it represents a potential vulnerability exploitable by senolytic agents.We established new patient-derived PA cell lines that preserve molecular features of the primary tumors and can be studied in OIS and proliferation depending on expression ore repression of the SV40 large T antigen. We determined expression of anti-apoptotic BCL-2 members in these models and primary PA. Dependence of senescent PA cells on anti-apoptotic BCL-2 members was investigated using a comprehensive set of BH3-mimetics.Senescent PA cells upregulate BCL-XL upon senescence induction and show dependency on BCL-XL for survival. BH3 mimetics with high affinity for BCL-XL (BCL-XLi) reduce metabolic activity and induce mitochondrial apoptosis in senescent PA cells at nano-molar concentrations. In contrast, BH3 mimetics without BCL-XLi activity, conventional chemotherapy and MEK inhibitors show no effect.Our data demonstrates that BCL-XL is critical for survival of senescent PA tumor cells and provides proof-of-principle for the use of clinically available BCL-XL-dependent senolytics.
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000181244 650_7 $$2Other$$aBCL-XL
000181244 650_7 $$2Other$$aBH3 mimetics
000181244 650_7 $$2Other$$aoncogene-induced senescence
000181244 650_7 $$2Other$$apilocytic astrocytoma
000181244 7001_ $$0P:(DE-He78)a5e60710c7515b3e1de74ced6928a9dd$$aSigaud, Romain$$b1$$udkfz
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000181244 7001_ $$aAlco, Clara$$b5
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000181244 7001_ $$aTsai, Jessica W$$b8
000181244 7001_ $$aGuiho, Romain$$b9
000181244 7001_ $$aMartínez-Barbera, Juan Pedro$$b10
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000181244 7001_ $$aDeng, Jing$$b12
000181244 7001_ $$aZhai, Yifan$$b13
000181244 7001_ $$0P:(DE-He78)a6b5fcabf661bef95109dbee87dc5271$$avan Tilburg, Cornelis Martinus$$b14$$udkfz
000181244 7001_ $$aSchuhman, Martin U$$b15
000181244 7001_ $$aDamaty, Ahmed E L$$b16
000181244 7001_ $$aBandopadhayay, Pratiti$$b17
000181244 7001_ $$aHerold-Mende, Christel$$b18
000181244 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b19$$udkfz
000181244 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b20$$udkfz
000181244 7001_ $$aMontero, Joan$$b21
000181244 7001_ $$0P:(DE-He78)51bf9ae9cb5771b30c483e5597ef606c$$aCapper, David$$b22$$udkfz
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000181244 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b24$$udkfz
000181244 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b25$$udkfz
000181244 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b26$$udkfz
000181244 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b27$$eLast author$$udkfz
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