UCSF

Although it was first observed nearly a century ago that transformed cells are marked by enlarged nucleoli, where ribosomal RNA synthesis and ribosome assembly occur, it has only recently become clear that deregulated protein synthesis plays a causal role in the development and progression of cancer. Indeed, aberrant mRNA translation has emerged as a hallmark of oncogenic transformation, underlying many cellular functions critical for tumorigenesis. Oncogenic signaling has been shown to enhance and alter the protein synthesis capacity of cancer cells to directly contribute to their survival, proliferation, metastasis, and genome instability. Therefore, inhibiting enhanced protein synthesis may represent a highly relevant strategy for the treatment of human cancers. For example, Myc is one of the most commonly deregulated oncogenes in human cancer, yet therapies directly targeting Myc hyperactivation are not presently available in the clinic. Although the ability to modulate protein synthesis control is critical to the Myc oncogenic program, components of the translation machinery that can be exploited as therapeutic targets for Myc-driven cancers remain poorly defined. Recently, the translation initiation factor eIF4E, which is considered the quantitatively rate limiting factor for translation initiation, has become a central focus for therapeutic approaches seeking to inhibit oncogenic activation of translation. Despite this, the requirements for eIF4E in normal mammalian development and physiology are largely unknown. Moreover, we still do not understand the specific roles that eIF4E plays in translating the genome of both normal and cancer cells.

Here, we uncover a surprising and important functional link between Myc and mammalian target of rapamycin (mTOR)-dependent phosphorylation of eukaryotic translation initiation factor 4E binding protein-1 (4EBP1), a master regulator of eIF4E-dependent protein synthesis control. Using a pharmacogenetic approach, we find that mTOR-dependent phosphorylation of 4EBP1 is required for cancer cell survival in Myc-dependent tumor initiation and maintenance. We further show that a clinical mTOR active site inhibitor, which is capable of blocking mTOR-dependent 4EBP1 phosphorylation, has remarkable therapeutic efficacy in Myc-driven hematological cancers. Moreover, we demonstrate the clinical implications of these results by delineating a significant link between Myc, mTOR-dependent phosphorylation of 4EBP1, and therapeutic response in human lymphomas. Together, these findings identify an important mTOR substrate hyperactivated downstream of Myc oncogenic activity, which promotes tumor cell survival and confers synthetic lethality, thereby revealing a unique therapeutic approach to render Myc druggable in the clinic.

Additionally, we have generated a novel Eif4e haploinsufficient mouse, allowing the requirements for eIF4E dose to be defined at the organismal level for the first time. Surprisingly, we find that a 50% reduction in eIF4E is compatible with normal development and global protein synthesis. Strikingly, however, Eif4e+/- cells and mice are remarkably resistant to oncogenic transformation. Unbiased genome-wide translational profiling of mRNAs induced by oncogenic transformation reveals eIF4E dosage is critical for translating key mRNA networks, including redox balance, signaling, and proteasome control, which are demarcated by a novel 5'UTR signature. In particular, eIF4E dose is essential for translating a novel class of mRNAs regulating reactive oxygen species (ROS), a hallmark of oncogene-induced stress. Translational control of intracellular ROS fuels cancer cell survival and underlies Eif4e+/- resistance to cellular transformation. Therefore, mammalian cells have evolved surplus eIF4E levels that are usurped by cancer cells to drive a translational program supporting tumor growth and survival.