Co-targeting CDK7/CDK9 and CKIα exerts efficacious anticancer effects against TERT gene-rearranged neuroblastoma

No targeted therapy is available for clinical trials in patients. Here we show that the transcriptional kinases CDK7/CDK9 and the casein kinase CKIα were required for TERT gene over-expression and p53 protein degradation respectively in TERT-rearranged neuroblastoma cells.

Co-knockdown of CDK7/CDK9 and CKIα or treatment with the CDK7/CDK9 and CKIα co-inhibitor A51 reduced TERT gene transcriptional initiation, elongation and expression, activated p53 protein expression, co-operatively induced apoptosis and suppressed tumor progression in mouse models. Screening of an approved oncology drug library identified Ceritinib as the agent exerting the best synergistic anticancer effects with A51.