Abstract
BACKGROUND/OBJECTIVES
MYC family proteins are implicated in many human cancers, but their therapeutic targeting has proven challenging. MYCN and c-MYC amplification in childhood neuroblastoma (NB) and medulloblastoma (MB) are associated with aggressive disease and high mortality. Novel and effective therapeutic strategies are therefore urgently needed for these tumors. MYC-driven oncogenic transformation impairs cell survival under nutrient deprivation (ND), a characteristic stress condition within the tumor microenvironment. We recently identified eukaryotic Elongation Factor 2 Kinase (eEF2K) as a pivotal mediator of the adaptive response of tumor cells to ND. We therefore hypothesized that eEF2K facilitates the adaptation of MYCN/MYC amplified NB/MB to ND, and that inhibiting this pathway can impair tumor progression.
METHODS
To test our hypothesis, we first analyzed publicly available genomic databases and tissue microarrays for eEF2K expression in NB and MB, and for links between eEF2K, MYCN/MYC, and clinical outcome. Effects of eEF2K inhibition were evaluated on survival of MYCN/MYC amplified versus non-amplified NB/MB cell lines under ND. Finally, NB xenograft mouse models were used to confirm in vitro observations.
RESULTS
Our results indicate that high eEF2K expression and activity are strongly predictive of poor outcome in NB and MB (p<0.001), and correlate significantly with MYCN/MYC amplification (p<0.001). Inhibition of eEF2K significantly decreases survival of MYCN/MYC amplified NB/MB cell lines in vitro under ND. Knockdown of eEF2K under caloric restriction determines a twofold growth decrease of MYCN amplified NB xenografts.
CONCLUSIONS
eEF2K represents a critical mediator for the adaptive response of MYCN/MYC amplified NB and MB to acute metabolic stress, and is therefore a promising therapeutic target. Future therapeutic studies will aim to combine eEF2K pharmacological inhibition with caloric restriction mimetics such as metformin or glycolysis inhibitors, as eEF2K activity appears to be critical under metabolic stress conditions.