Abstract
MYC is a central driver of tumorigenesis in many malignancies, including the universally lethal glioblastoma (GBM). However, developing direct inhibitors of MYC have proven challenging. One appealing alternative strategy to target MYC-driven cancers is to interfere with the signaling program necessary to facilitate MYC-dependent transcription. Cyclin-dependent kinase 9 (CDK9) has emerged as an attractive candidate through its function as a critical regulator in the transcriptional elongation of MYC and its target genes. Using a panel of patient-derived GBM cells, here we demonstrate that CDK9 inhibition with the brain-penetrant multi-CDK inhibitor, TG02, potently suppresses GBM cell growth. Importantly, the anti-GBM efficacy of TG02 strongly correlates with MYC expression and appears to be independent of methylation status, suggesting a critical role for CDK9 in MYC-driven GBMs. These preliminary results indicate that CDK9 may be an actionable therapeutic target in GBM with aberrant MYC signaling and, importantly, the clinical stage oral small molecule, TG02, is an appealing drug candidate for GBM with elevated MYC activity. Ongoing in vivo efficacy studies are evaluating TG02 in clinically relevant MYC-driven GBM mouse models.