Target:
Medulloblastoma (MB) is a prevalent childhood cerebellar malignancy, with MYC-amplified Group 3 tumors having the worst prognosis. MYC, an oncogenic transcription factor, is typically considered undruggable. However, targeting MYC-dependent processes, such as transcription and RNA processing regulation, offers promise.
In this study, MYC-driven Group 3 MB cells were tested for sensitivity to a range of transcription and splicing inhibitors, with a focus on THZ531, a CDK12/13 inhibitor. High-throughput RNA sequencing and bioinformatics analyses revealed that CDK12/13 inhibition selectively affects MYC-high Group 3 MB cells. Genes related to the DNA damage response (DDR) were up-regulated in Group 3 MB and repressed by CDK12/13 inhibition. CDK12/13 inhibition induced irreparable DNA damage in MYC-high Group 3 MB cells, particularly due to the higher RNA polymerase II elongation rate in DDR genes. Combining THZ531 with DNA damage-inducing agents effectively reduced the viability of MYC-high Group 3 MB cells.
This study identifies CDK12/13 as an exploitable vulnerability in MYC-high Group 3 MB, suggesting new therapeutic possibilities for this high-risk brain tumor.