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

• DOI: 10.1038/s41418-022-01001-3
• Publication Date: 2022-04-26T18:07:57Z
• Authors: Anna L. Koessinger; Catherine Cloix; Dominik Koessinger; Dieter Henrik Hei...; Florian J. Bock; Karen Strathdee; Kevin Kinch; Laura Martínez-Es...; Nikki R. Paul; Colin Nixon; Gaurav Malviya; Mark R. Jackson; Kirsteen J. Campbell; Katrina 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
• Keywords: Bcl-xL; Priming (agriculture)

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