Abstract
CK2 is an antiapoptotic kinase overactive in various malignancies. Here we show that CK2 inhibition dramatically affects neuroblastoma growth both in vitro and in vivo. In particular, here we report on the identification of CK2-TN03, a CK2 inhibitor showing greater selectivity and cellular efficacy than silmitasertib, the only available clinical grade CK2 inhibitor with orphan status for cholangiocarcinoma and in clinical trials for medulloblastoma. CK2-TN03 acts by suppressing survivin, which is overexpressed in all high-risk neuroblastomas. Survivin function is affected by direct inhibition of its phosphorylation by CK2; its messenger RNA and protein levels are reduced through CK2 regulation of the MDM2/p53 balance via AKT1 and BRD4/MYCN. Accordingly, neuroblastoma cells persistently stall in mitosis before going to apoptosis. Finally, CK2-TN03 does not affect noncycling cells and significantly reduces tumor growth in mice xenografts without any apparent toxicity.