Targeting Synthetic Lethal Interactions between Myc and the eIF4F Complex Impedes Tumorigenesis

SummaryThe energetically demanding process of translation is linked to multiple signaling events through mTOR-mediated regulation of eukaryotic initiation factor (eIF)4F complex assembly. Disrupting mTOR constraints on eIF4F activity can be oncogenic and alter chemotherapy response, making eIF4F an attractive antineoplastic target. Here, we combine a newly developed inducible RNAi platform and pharmacological targeting of eIF4F activity to define a critical role for endogenous eIF4F in Myc-dependent tumor initiation. We find elevated Myc levels are associated with deregulated eIF4F activity in the prelymphomatous stage of the Eμ-Myc lymphoma model. Inhibition of eIF4F is synthetic lethal with elevated Myc in premalignant pre-B/B cells resulting in reduced numbers of cycling pre-B/B cells and delayed tumor onset. At the organismal level, eIF4F suppression affected a subset of normal regenerating cells, but this was well tolerated and rapidly and completely reversible. Therefore, eIF4F is a key Myc client that represents a tumor-specific vulnerability.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Elevated eIF4F levels are a premalignant feature of Eμ-Myc lymphomas ► Transient eIF4E suppression delays tumor initiation in Myc-induced lymphomas ► A novel inducible RNAi platform demonstrates that eIF4F is a client of Myc in vivo ► Elevated Myc levels and eIF4F suppression show a synthetic lethal relationship