Abstract 5395: CDK12 regulates cellular metabolism to promote therapy resistance in glioblastoma

Abstract Glioblastoma IDH-wildtype, the most common primary brain cancer in adults, has an exceedingly poor prognosis of only one to two years despite standard treatment involving surgery, temozolomide, and radiation. We evaluated patient-derived xenograft GBM cultures to determine their sensitivity to disrupting the function of CDK12, which was achieved through genetic manipulation, shRNA, or the novel inhibitor SR-4835. GBM metabolism was assessed using extracellular flux analysis and LC/MS-based carbon tracing. The in vivo efficacy was evaluated in orthotopic GBM mouse models. Comprehensive screening approaches identified CDK12 as essential for GBM growth. Consistently, inhibiting CDK12 function led to reduced growth in GBM PDX lines in vitro, but not in human astrocytes. Notably, SR-4835 inhibited GBM growth at low nanomolar concentrations and synergistically enhanced the potency of temozolomide. In vivo, SR-4835 activated cell death machinery related to intrinsic apoptosis. Metabolic analyses demonstrated that the loss of CDK12 function substantially impaired cellular respiration, coupled with the suppression of key metabolic transcriptional regulators, PGC1A and PPARD. This resulted in energy depletion and apoptotic cell death, partially mediated by the pro-apoptotic protein Noxa. The inactivation of CDK12 significantly extended the overall survival time without any harmful side effects in orthotopic mouse models of GBM. In some subjects, it also led to the complete elimination of brain tumors. When used together with temozolomide, blocking CDK12 eradicated brain tumors in all animals studied, indicating that CDK12 is a highly promising treatment target for GBM and providing a solid foundation for future clinical trials involving patients with this devastating disease. Citation Format: Jeong-Yeon Mun, Chang Shu, Qiuqiang Gao, Hasan O. Akman, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin. CDK12 regulates cellular metabolism to promote therapy resistance in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5395.