Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics

Koessinger AL, Cloix C, Koessinger D, Heiland DH, Bock FJ, Strathdee K, Kinch K, Martínez-Escardó L, Paul NR, Nixon C, Malviya G, Jackson MR, Campbell KJ, Stevenson K, Davis S, Elmasry Y, Ahmed A, O’Prey J, Ichim G, Schnell O, Stewart W, Blyth K, Ryan KM, Chalmers AJ, Norman JC, Tait SW (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Cell Death and Differentiation Nature Publishing Group: Open Access Hybrid Model Option B

Book Volume: 29

Pages Range: 2089-2104

Journal Issue: 10

DOI: 10.1038/s41418-022-01001-3

Abstract

Glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. We investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti-apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non-malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti-apoptotic BCL-2 family members. High anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein-targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3-mimetics.

Authors with CRIS profile

Dieter Henrik Heiland
Oliver Schnell

Involved external institutions

Cancer Research UK Beatson Institute GB United Kingdom (GB) Universitätsklinikum Freiburg DE Germany (DE) National Center for Scientific Research / Centre national de la recherche scientifique (CNRS) FR France (FR) Queen Elizabeth University Hospital GB United Kingdom (GB) University of Glasgow GB United Kingdom (GB)

How to cite

APA:

Koessinger, A.L., Cloix, C., Koessinger, D., Heiland, D.H., Bock, F.J., Strathdee, K.,... Tait, S.W. (2022). Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics. Cell Death and Differentiation, 29(10), 2089-2104. https://doi.org/10.1038/s41418-022-01001-3

MLA:

Koessinger, Anna L., et al. "Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics." Cell Death and Differentiation 29.10 (2022): 2089-2104.

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