%0 Journal Article
%A Selt, Florian
%A Sigaud, Romain
%A Valinciute, Gintvile
%A Sievers, Philipp
%A Zaman, Julia
%A Alco, Clara
%A Schmid, Simone
%A Peterziel, Heike
%A Tsai, Jessica W
%A Guiho, Romain
%A Martínez-Barbera, Juan Pedro
%A Pusch, Stefan
%A Deng, Jing
%A Zhai, Yifan
%A van Tilburg, Cornelis Martinus
%A Schuhman, Martin U
%A Damaty, Ahmed E L
%A Bandopadhayay, Pratiti
%A Herold-Mende, Christel
%A von Deimling, Andreas
%A Pfister, Stefan
%A Montero, Joan
%A Capper, David
%A Oehme, Ina
%A Sahm, Felix
%A Jones, David
%A Witt, Olaf
%A Milde, Till
%T BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.
%J Neuro-Oncology
%V 25
%N 4
%@ 1522-8517
%C Oxford
%I Oxford Univ. Press
%M DKFZ-2022-01890
%P 735-747
%D 2023
%Z #EA:B310#LA:B310# / 2023 Apr 6;25(4):735-747
%X 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.
%K BCL-XL (Other)
%K BH3 mimetics (Other)
%K oncogene-induced senescence (Other)
%K pilocytic astrocytoma (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:35977048
%R 10.1093/neuonc/noac199
%U https://inrepo02.dkfz.de/record/181244