Neuroblastoma and medulloblastoma, malignant tumors of the nervous system, are the most common childhood solid tumors and leading cause of childhood related cancer deaths. A subset of these tumors, collectively characterized by MYC of MYCN amplification or overexpression, bears dismal prognosis with a ten-year survival rate around 50%. However, the discovery of molecularly informed targeted therapies represents a major challenge in current cancer research, and these are currently unavailable for children affected by neuroblastoma and medulloblastoma. It is sobering that for most children who suffer relapse, there are few if any therapeutic options available, with most patients receiving the same type of therapy that failed in the first place.
While MYC-driven oncogenic transformation is known to determine adverse patient outcome, it also induces a high metabolic demand that impairs cell survival under acute nutrient deprivation (ND). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, is critical for cell adaptation to ND. We therefore set out to determine if eEF2K is required for the progression of MYC-driven childhood cancer. Our in vitro and in vivo results revealed that MYCN and MYC driven neuroblastoma and medulloblastoma rely on eEF2K to overcome nutrient starvation. We surveyed clinical samples of neuroblastoma and medulloblastoma, and we observed high eEF2K activity to be significantly associated with MYC family members overexpression. Mechanistically, through multiple proteomics experiments coupled with RNAseq, we found that eEF2K regulates the synthesis of several components of the mitochondrial electron transport chain. As a result, eEF2K deficient cells displayed inefficient super complex assembly and oxidative phosphorylation.
Overall, our work identifies novel targetable pathways contributing to the progression of MYC driven neuronal tumors. Future studies should investigate the combination of eEF2K inhibition with caloric restriction mimetics, as a targeted therapeutic approach for MYC driven tumors.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat
