Journal Article

DKFZ-2022-01890

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.

Selt, F. (First author)DKFZ* ; Sigaud, R.DKFZ* ; Valinciute, G.DKFZ* ; Sievers, P.DKFZ* ; Zaman, J.DKFZ* ; Alco, C. ; Schmid, S.DKFZ* ; Peterziel, H.DKFZ* ; Tsai, J. W. ; Guiho, R. ; Martínez-Barbera, J. P. ; Pusch, S.DKFZ* ; Deng, J. ; Zhai, Y. ; van Tilburg, C. M.DKFZ* ; Schuhman, M. U. ; Damaty, A. E. L. ; Bandopadhayay, P. ; Herold-Mende, C. ; von Deimling, A.DKFZ* ; Pfister, S.DKFZ* ; Montero, J. ; Capper, D.DKFZ* ; Oehme, I.DKFZ* ; Sahm, F.DKFZ* ; Jones, D.DKFZ* ; Witt, O.DKFZ* ; Milde, T. (Last author)DKFZ*

2023
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/neuonc/noac199

Abstract: 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.

Keyword(s): BCL-XL ; BH3 mimetics ; oncogene-induced senescence ; pilocytic astrocytoma

Note: #EA:B310#LA:B310# / 2023 Apr 6;25(4):735-747

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Contributing Institute(s):

1. KKE Pädiatrische Onkologie (B310)
2. DKTK HD zentral (HD01)
3. KKE Neuropathologie (B300)
4. DKTK BE zentral (BE01)
5. B062 Pädiatrische Neuroonkologie (B062)
6. Pediatric Glioma (B360)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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