Abstract Background: Resistance to mitochondrial apoptosis contributes to treatment failure in IDH-wildtype glioblastoma (GBM). Cyclin-dependent kinase 12 (CDK12) regulates transcriptional programs that sustain tumor survival, but its role in apoptotic control is largely unclear. Methods: CDK12 was inhibited in GBM patient-derived xenografts, stem-like cells, and established lines by genetic depletion or the small-molecule SR-4835. Bcl-xL was targeted using the BH3 mimetic ABT-263 (navitoclax). Viability, apoptosis, and mechanistic endpoints were assessed by combination index analysis, caspase activity, immunoblotting, and gene silencing. Results: Co-treatment with SR-4835 and ABT-263 produced a synergistic loss of viability across GBM models (combination index 0.5), whereas either agent alone had minimal effects. This synergy was associated with enhanced cleavage of initiator and effector caspases and was fully rescued by the pan-caspase inhibitor zVAD-fmk, confirming caspase-dependent apoptosis. Mechanistically, CDK12 blockade downregulated the anti-apoptotic protein Mcl-1 and induced the pro-apoptotic BH3-only protein Noxa through activation of an ATF4-driven integrated stress response (ISR). Silencing ATF4 blunted SR-4835-induced Noxa expression, and Noxa knockdown significantly reduced apoptosis triggered by the combination, demonstrating its essential role in the response. Conclusions: CDK12 inhibition activates an ISR-ATF4-Noxa signaling axis that lowers the apoptotic threshold and sensitizes GBM cells to Bcl-xL inhibition. Dual targeting of CDK12 and Bcl-xL represents a mechanistically defined strategy to overcome apoptosis resistance in GBM and may have broader therapeutic relevance across malignancies driven by Mcl-1-mediated survival. Citation Format: Jeong-Yeon Mun, Chang Shu, Emily Hsia, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus David Siegelin. JM abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3177.
Mun et al. (Fri,) studied this question.