Selt, Florian;
Sigaud, Romain;
Valinciute, Gintvile;
Sievers, Philipp;
Zaman, Julia;
Alco, Clara;
Schmid, Simone;
... Milde, Till; + view all
(2023)
BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.
Neuro-Oncology
, 25
(4)
pp. 735-747.
10.1093/neuonc/noac199.
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Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
| Type: | Article |
|---|---|
| Title: | BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1093/neuonc/noac199 |
| Publisher version: | https://doi.org/10.1093/neuonc/noac199 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. |
| Keywords: | BCL-XL, BH3 mimetics, oncogene-induced senescence, pilocytic astrocytoma |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10161671 |
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