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)
![[img]](https://eprints.gla.ac.uk/style/images/fileicons/text.png) |
Text
269006.pdf - Published Version Available under License Creative Commons Attribution. 6MB |
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 Malviya, Dr Gaurav 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, Dr 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 |
| 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 |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information