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| 001 | 181244 | ||
| 005 | 20240229145643.0 | ||
| 024 | 7 | _ | |a 10.1093/neuonc/noac199 |2 doi |
| 024 | 7 | _ | |a pmid:35977048 |2 pmid |
| 024 | 7 | _ | |a 1522-8517 |2 ISSN |
| 024 | 7 | _ | |a 1523-5866 |2 ISSN |
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| 037 | _ | _ | |a DKFZ-2022-01890 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Selt, Florian |0 P:(DE-He78)a23e88cc676489fe05be8c178ceaf58e |b 0 |e First author |u dkfz |
| 245 | _ | _ | |a BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma. |
| 260 | _ | _ | |a Oxford |c 2023 |b Oxford Univ. Press |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1681202819_5541 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a #EA:B310#LA:B310# / 2023 Apr 6;25(4):735-747 |
| 520 | _ | _ | |a Pilocytic 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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| 650 | _ | 7 | |a BCL-XL |2 Other |
| 650 | _ | 7 | |a BH3 mimetics |2 Other |
| 650 | _ | 7 | |a oncogene-induced senescence |2 Other |
| 650 | _ | 7 | |a pilocytic astrocytoma |2 Other |
| 700 | 1 | _ | |a Sigaud, Romain |0 P:(DE-He78)a5e60710c7515b3e1de74ced6928a9dd |b 1 |u dkfz |
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| 700 | 1 | _ | |a Alco, Clara |b 5 |
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| 700 | 1 | _ | |a Peterziel, Heike |0 P:(DE-He78)2727b5cb63b52d0137d4f4e8f110ee7e |b 7 |u dkfz |
| 700 | 1 | _ | |a Tsai, Jessica W |b 8 |
| 700 | 1 | _ | |a Guiho, Romain |b 9 |
| 700 | 1 | _ | |a Martínez-Barbera, Juan Pedro |b 10 |
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| 700 | 1 | _ | |a Damaty, Ahmed E L |b 16 |
| 700 | 1 | _ | |a Bandopadhayay, Pratiti |b 17 |
| 700 | 1 | _ | |a Herold-Mende, Christel |b 18 |
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| 700 | 1 | _ | |a Milde, Till |0 P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f |b 27 |e Last author |u dkfz |
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