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BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma
Florian Selt 1 2 3, Romain Sigaud 1 2, Gintvile Valinciute 1 2, Philipp Sievers 4 5, Julia Zaman 4 5, Clara Alco 6, Simone Schmid 7 8, Heike Peterziel 1 2, Jessica W Tsai 9, Romain Guiho 10, Juan Pedro Martínez-Barbera 10, Stefan Pusch 4 5, Jing Deng 11, Yifan Zhai 11, Cornelis M van Tilburg 1 2 3, Martin U Schuhman 12, Ahmed E L Damaty 13, Pratiti Bandopadhayay 9 14 15, Christel Herold-Mende 16, Andreas von Deimling 4 5, Stefan M Pfister 1 17, Joan Montero 6, David Capper 7 8, Ina Oehme 1 2, Felix Sahm 1 4 5, David T W Jones 1 18, Olaf Witt 1 2 3, Till Milde 1 2 3
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.
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.
PMID: 35977048
SENS Approach:
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