BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2023-04, Vol.25 (4), p.735-747
• Main Authors: Selt, Florian, Sigaud, Romain, Valinciute, Gintvile, Sievers, Philipp, Zaman, Julia, Alcon, Clara, Schmid, Simone, Peterziel, Heike, Tsai, Jessica W, Guiho, Romain, Martínez-Barbera, Juan Pedro, Pusch, Stefan, Deng, Jing, Zhai, Yifan, van Tilburg, Cornelis M, Schuhman, Martin U, El Damaty, Ahmed, Bandopadhayay, Pratiti, Herold-Mende, Christel, von Deimling, Andreas, Pfister, Stefan M, Montero, Joan, Capper, David, Oehme, Ina, Sahm, Felix, Jones, David T W, Witt, Olaf, Milde, Till
• Format: Article
• Language: English
• Subjects: Apoptosis; Astrocytoma - pathology; Brain Neoplasms - pathology; Cell Line, Tumor; Child; Humans; Mitogen-Activated Protein Kinases; Pediatric Neuro-Oncology; Proto-Oncogene Proteins c-bcl-2
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noac199

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 antiproliferative 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 or 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 demonstrate 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.