Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics
Anna L. Koessinger, Catherine Cloix, Dominik Koessinger, Dieter Henrik Heiland, Florian J. Bock, Karen Strathdee, Kevin Kinch, Laura Martínez‐Escardó, Nikki R. Paul, Colin Nixon, Gaurav Malviya, Mark R. Jackson, Kirsteen J. Campbell, Katrina H. Stevenson, Sandeep Davis, Yassmin Elmasry, Asma Ahmed, Jim O’Prey, Gabriel Ichim, Oliver Schnell, William Stewart, Karen Blyth, Kevin M. Ryan, Anthony J. Chalmers, Jim C. Norman, Stephen W. G. Tait
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.