Abstract
Glioblastoma IDH-wildtype is the most common and aggressive primary brain tumor in adults, with poor prognosis despite current therapies. To identify new therapeutic vulnerabilities, we investigated the role of CDK12, a transcription-associated cyclin-dependent kinase, in glioblastoma. Genetic or pharmacologic inactivation of CDK12 impaired tumor growth in patient-derived xenograft (PDX) models and enhanced the efficacy of temozolomide. Metabolic profiling using extracellular flux analysis and stable isotope tracing with U-¹³C-glucose and U-¹³C-glutamine showed that CDK12 inhibition disrupted mitochondrial respiration, resulting in energy depletion and apoptotic cell death characterized by caspase activation and Noxa induction. Mechanistically, we identified a direct interaction between CDK12 and GSK3β. CDK12 inhibition activated GSK3β, leading to downregulation of PPARD, a transcriptional regulator of oxidative metabolism. This CDK12/GSK3β/PPARD axis was required for glioblastoma cell proliferation and metabolic homeostasis. In vivo, CDK12 inhibition significantly extended survival without overt toxicity and induced complete tumor regression in a subset of animals. Strikingly, combined CDK12 inhibition and temozolomide treatment led to complete tumor eradication in all animals tested. These findings establish CDK12 as a key regulator of glioblastoma metabolism and survival, and provide strong preclinical rationale for its therapeutic targeting in combination with standard-of-care treatments.
Authors
Jeong-Yeon Mun, Chang Shu, Qiuqiang Gao, Zhe Zhu, Hasan O. Akman, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D. Siegelin
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