TY  - JOUR
AU  - Selt, Florian
AU  - Sigaud, Romain
AU  - Valinciute, Gintvile
AU  - Sievers, Philipp
AU  - Zaman, Julia
AU  - Alco, Clara
AU  - Schmid, Simone
AU  - Peterziel, Heike
AU  - Tsai, Jessica W
AU  - Guiho, Romain
AU  - Martínez-Barbera, Juan Pedro
AU  - Pusch, Stefan
AU  - Deng, Jing
AU  - Zhai, Yifan
AU  - van Tilburg, Cornelis Martinus
AU  - Schuhman, Martin U
AU  - Damaty, Ahmed E L
AU  - Bandopadhayay, Pratiti
AU  - Herold-Mende, Christel
AU  - von Deimling, Andreas
AU  - Pfister, Stefan
AU  - Montero, Joan
AU  - Capper, David
AU  - Oehme, Ina
AU  - Sahm, Felix
AU  - Jones, David
AU  - Witt, Olaf
AU  - Milde, Till
TI  - BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.
JO  - Neuro-Oncology
VL  - 25
IS  - 4
SN  - 1522-8517
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2022-01890
SP  - 735-747
PY  - 2023
N1  - #EA:B310#LA:B310# / 2023 Apr 6;25(4):735-747
AB  - 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.
KW  - BCL-XL (Other)
KW  - BH3 mimetics (Other)
KW  - oncogene-induced senescence (Other)
KW  - pilocytic astrocytoma (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:35977048
DO  - DOI:10.1093/neuonc/noac199
UR  - https://inrepo02.dkfz.de/record/181244
ER  -