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

Koessinger, A. L. et al. (2022) Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics. Cell Death and Differentiation, 29(10), pp. 2089-2104. (doi: 10.1038/s41418-022-01001-3) (PMID:35473984) (PMCID:PMC9525582)

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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.

Item Type:Articles
Additional Information:This work was supported by CRUK core funding to the Beatson Institute (A17196) to C.N., (A17196/A31287) to N.R.P., (A22903) to K.M.R. and J.O’P., and (A18277) to J.C.N., a CRUK Programme Foundation Award (C40872/A20145) to S.W.T., CRUK Clinical Research Fellowship (A23220) to A.L.K., funding by the University of Glasgow to D.K. and A.J.C. and funding by the Beatson Cancer Charity and Cancer Research UK RadNet Centre Glasgow (A28803) to K.S., S.D. and K.S.. L.M.-E. was funded by the by Erasmus+ Program and Short Research stay fellowship for trainees by Universitat Autònoma de Barcelona and A.A. by Prostate Cancer UK RIA17-ST2-002. DHH is funded by the Else Kröner-Fresenius Foundation. The work is part of the MEPHISTO project, funded by BMBF (iGerman Ministry of Education and Research, project number: 031L0260B).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bock, Dr Florian and Paul, Dr Nikki and Stewart, Dr William and Blyth, Professor Karen and Elmasry, Ms Yassmin and Ichim, Dr Gabriel and Cloix, Dr Catherine and Norman, Professor James and Kinch, Dr Kevin and Jackson, Dr Mark and Ryan, Professor Kevin and Stevenson, Mrs Katrina and Ahmed Hassan Elshiekh, Mrs Asma and O'Prey, Mr James and Nixon, Mr Colin and Koessinger, Anna Laura and Strathdee, Mrs Karen and Tait, Professor Stephen and Koessinger, Dr Dominik and Davis, Mrs Sandeep and Chalmers, Professor Anthony and Malviya, Dr Gaurav
Authors: Koessinger, A. L., Cloix, C., Koessinger, D., Heiland, D. H., Bock, F. J., Strathdee, K., Kinch, K., Martínez-Escardó, L., Paul, N. R., Nixon, C., Malviya, G., Jackson, M. R., Campbell, K. J., Stevenson, K., Davis, S., Elmasry, Y., Ahmed, A., O'Prey, J., Ichim, G., Schnell, O., Stewart, W., Blyth, K., Ryan, K. M., Chalmers, A. J., Norman, J. C., and Tait, S.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Cell Death and Differentiation
Publisher:Springer Nature
ISSN:1350-9047
ISSN (Online):1476-5403
Published Online:26 April 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cell Death and Differentiation 29(10): 2089-2104
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172007Apoptosis as an oncogenic process: understanding and exploiting its dark-sideStephen TaitCancer Research UK (CRUK)C40872/A20145Institute of Cancer Sciences
172980CRUK Glasgow Centre Clinical Training AwardStephen TaitCancer Research UK (CRUK)C596/A23220Institute of Cancer Sciences
306407Glasgow RadNet CentreAnthony ChalmersCancer Research UK (CRUK)C16583/A28803CS - Clinical Trials Research
301861Targeting immunogenic cell death to treat prostate cancerStephen TaitProstate Cancer UK (PROSCANU)RIA17-ST2-002CS - Beatson Institute for Cancer Research