Increased apoptotic priming of glioblastoma enables therapeutic targeting by BH3-mimetics
Koessinger, A.; Koessinger, D.; Kinch, K.; Martinez-Escardo, L.; Paul, N.; Elmasry, Y.; Malviya, G.; Cloix, C.; Campbell, K.; Bock, F.; O'Prey, J.; Stevenson, K.; Nixon, C.; Jackson, M.; Ichim, G.; Stewart, W.; Blyth, K.; Ryan, K.; Chalmers, A. J.; Norman, J.; Tait, S.
Show abstract
IDH wild-type 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. Tackling this, 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. Surprisingly, 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.
Matching journals
The top 11 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Purine metabolism regulates DNA repair and therapy resistance in glioblastoma 95%
- Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma 95%
- Cancer avatars derived from genetically engineered pluripotent stem cells allow for longitudinal assessment of tumor development 95%
Similar papers in this journal
- Therapy-induced transdifferentiation promotes glioma growth independent of EGFR signaling 96%
- Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery in Glioblastoma. 95%
- NRF2 translation block by inhibition of cap-dependent initiation sensitizes lymphoma cells to ferroptosis and CAR-T immunotherapy 95%
Similar papers in this journal
- SLIT2-ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia 97%
- Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition 97%
- IL-7-mediated expansion of autologous lymphocytes increases CD8+ VLA-4 expression and accumulation in glioblastoma models 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.