Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX?histone chaperone complex and that induced by MYCN-mediated metabolic reprogramming leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. In this proposal, we will exploit this synthetic lethality to improve outcomes for patients with high-risk and/or recurrent neuroblastoma. Specifically, we will use molecular targeted therapeutics to perturb ATRX-dependent processes in MYCN amplified neuroblastomas and to disrupt MYCN-dependent processes in ATRX deficient tumors. In this translational research proposal, we will target both the tumor cells and the tumor microenvironment. All published and unpublished data are freely shared through the Childhood Solid Tumor Network to accelerate discovery on neuroblastoma. The results of these studies will be used to design the next neuroblastoma clinical trials at St. Jude.
We have discovered that MYCN amplification and ATRX-mutations are synthetic lethal in neuroblastoma (NB). In this project, we will suppress ATRX pathway function in MYCN amplified NB and mimic key aspects of MYCN amplification in ATRX-mutant tumors. Discoveries from this study will be directly translated into clinical trials in children with NB at St. Jude.
