BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma
Florian Selt, Romain Sigaud, Gintvile Valinciute, Philipp Sievers, Julia Zaman, Clara Alcon, Simone Schmid, Heike Peterziel, Jessica W. Tsai, Romain Guiho, Juan Pedro Martı́nez-Barberá, Stefan Pusch, Jing Deng, Yifan Zhai, Cornelis M. van Tilburg, Martin U Schuhman, Ahmed El Damaty, Pratiti Bandopadhayay, Christel Herold‐Mende, Andreas von Deimling, Stefan M. Pfister, Joan Montero, David Capper, Ina Oehme, Felix Sahm, David Jones, Olaf Witt, Till Milde
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.