Abstract A46: Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers

Myc is one of the most highly activated oncogenes in human cancer, yet therapeutic approaches to directly target Myc are not currently available in the clinic. The evolutionarily conserved function of Myc in regulating ribosome biogenesis and protein synthesis is critical for the Myc oncogenic program. Indeed, deregulated control of mRNA translation leads to increased cellular proliferation, survival and genomic instability during Myc tumorigenesis. Therefore, inhibiting enhanced protein synthesis may represent an attractive strategy for the treatment of Myc-dependent cancers. To this end, we asked if specific components of the protein synthesis machinery could be effective therapeutic targets in Myc-driven cancers. We uncovered a novel functional link between Myc and increased mammalian Target of Rapamycin (mTOR) kinase-dependent phosphorylation of eukaryotic translation initiation factor 4E binding protein (4EBP1), a master regulator of protein synthesis. Specifically, we found in a transgenic model of Myc-driven lymphoma that oncogenic Myc activates mTOR-dependent phosphorylation of 4EBP1 prior to tumor formation while phosphorylation of other mTOR substrates is not increased. Employing a pharmacogenetic approach, we found that mTOR-dependent 4EBP1 phosphorylation is required for cellular survival during Myc-dependent tumor initiation and maintenance. Furthermore, we demonstrated the preclinical efficacy of a newly developed clinical mTOR active site inhibitor MLN0128, which is capable of fully blocking 4EBP1 phosphorylation, in Myc-driven hematologic malignancies. We found that MLN0128 significantly prolonged survival compared to treatment with vehicle or the allosteric mTOR inhibitor, RAD001, which was incapable of inhibiting 4EBP1 phosphorylation. Additionally, we extended the implications of our findings to human diffuse large B-cell lymphomas by demonstrating that high Myc expression correlated with increased phosphorylation of 4EBP1 in a large cohort of patients. Ongoing work will determine the specific translationally regulated mRNAs downstream of 4EBP1-eIF4E that are required for survival of Myc-overexpressing tumors and elucidate the mechanism by which Myc overexpression leads to increased mTOR-dependent phosphorylation of 4EBP1. Together, our findings reveal that an important mTOR substrate is found hyperactivated downstream of Myc oncogenic activity to promote tumor survival and confers synthetic lethality, thereby revealing a unique therapeu