MYC up-regulation confers vulnerability to dual inhibition of CDK12 and CDK13 in high-risk Group 3 medulloblastoma

MYC up-regulation confers vulnerability to dual inhibition of CDK12 and CDK13 in high-risk Group 3 medulloblastoma

Blog Article

Abstract Background Medulloblastoma (MB) is the most common cerebellar malignancy during childhood.Among MB, MYC-amplified Group 3 tumors display the worst prognosis.MYC is an oncogenic transcription factor currently thought to be undruggable.Nevertheless, targeting MYC-dependent processes (i.e.

transcription and RNA processing regulation) represents a promising approach.Methods We have tested the sensitivity of MYC-driven Group 3 MB cells to a pool of transcription and splicing inhibitors that display a wide spectrum of targets.Among them, we focus on THZ531, an inhibitor of the transcriptional cyclin-dependent kinases (CDK) 12 and 13.High-throughput RNA-sequencing analyses followed by bioinformatics and functional analyses were carried out to elucidate the molecular mechanism(s) underlying the susceptibility of Group 3 MB to CDK12/13 chemical inhibition.Data from International Cancer Genome Consortium (ICGC) and other public databases were mined to evaluate the Shampoos functional relevance of the cellular pathway/s affected by the treatment with THZ531 in Group 3 MB patients.

Results We found that pharmacological inhibition of CDK12/13 is highly selective for MYC-high Group 3 MB cells with respect to MYC-low MB cells.We identified a subset of genes enriched in functional terms related to the DNA damage response (DDR) that are up-regulated in Group 3 MB and repressed by CDK12/13 inhibition.Accordingly, MYC- and CDK12/13-dependent higher expression of DDR genes in Group 3 MB cells limits the toxic effects of endogenous DNA lesions in these cells.More importantly, chemical inhibition of CDK12/13 impaired the DDR and induced irreparable DNA damage exclusively in MYC-high Group 3 MB cells.The augmented sensitivity of MYC-high MB cells to CDK12/13 inhibition relies on the higher Medium Plate elongation rate of the RNA polymerase II in DDR genes.

Lastly, combined treatments with THZ531 and DNA damage-inducing agents synergically suppressed viability of MYC-high Group 3 MB cells.Conclusions Our study demonstrates that CDK12/13 activity represents an exploitable vulnerability in MYC-high Group 3 MB and may pave the ground for new therapeutic approaches for this high-risk brain tumor.