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

TERT gene rearrangement with transcriptional super-enhancers leads to substantial TERT over-expression and 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. A51 and Ceritinib synergistically down-regulated mitochondrial complex I gene expression and induced oxidative stress and TERT-rearranged neuroblastoma cell apoptosis. In mice xenografted with TERT-rearranged patient-derived xenograft neuroblastoma cells, A51 and Ceritinib synergistically induced tumor cell apoptosis, suppressed tumor progression and improved mouse survival. A51 and Ceritinib combination therapy is therefore a good candidate for translation into the first clinical trial of a targeted therapy against TERT-rearranged neuroblastoma.