期刊
CELL DEATH AND DIFFERENTIATION
卷 29, 期 10, 页码 2089-2104出版社
SPRINGERNATURE
DOI: 10.1038/s41418-022-01001-3
关键词
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资金
- CRUK [A17196, A29799, A17196/A31287, A22903, JO'P, A18277]
- CRUK Programme Foundation Award [C40872/A20145]
- CRUK Clinical Research Fellowship [A23220]
- University of Glasgow
- Beatson Cancer Charity [A28803]
- Universitat Autonoma de Barcelona
- Prostate Cancer UK [RIA17-ST2-002]
- Else Kroner-Fresenius Foundation - BMBF (iGerman Ministry of Education and Research) [031L0260B]
This study investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in glioblastoma (GBM), the most common malignant brain tumor in adults. The study found that the expression levels of anti-apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non-malignant cells and tissue. Furthermore, patient-derived GBM stem-like cells also displayed higher expression of anti-apoptotic BCL-2 family members. Sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumor responses in vivo.
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.
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