A novel druggable DYRK3/CAMKV signaling module for Neuroblastoma tumor growth inhibition.

High-risk Neuroblastoma is a very aggressive and deadly pediatric cancer, accounting for over 15% of all childhood cancer mortality. Therefore, novel therapeutic strategies for the treatment of neuroblastoma are urgently sought for. Here, we identified the DYRK3 kinase as a critical mediator of neuroblastoma cell proliferation and in vivo tumor growth. Our data suggest a role for DYRK3 as a regulator of the neuroblastoma-specific protein CAMKV, which is also required for neuroblastoma cell proliferation. We show that CAMKV is phosphorylated by DYRK3, and that inhibition of DYRK3 kinase activity induces CAMKV aggregation, probably mediated by its highly disordered C-terminal half. Importantly, we provide evidence that the DYRK3/CAMKV signaling module could play an important role in the regulation of the mitotic spindle during cell division, supporting the idea that inhibition of DYRK3 and/or CAMKV in neuroblastoma cells could constitute an innovative and highly specific intervention to fight against this dreadful pediatric cancer.