Summary Colorectal cancer (CRC) represents a leading cause of cancer death in the US and worldwide, and its development is driven by mutational activation of Wnt, RAS/RAF/ERK and PI3K/AKT/mTOR signaling. However, targeting individual driver in CRC has limited success. Wnt, mTOR and ERK signaling converges to deregulate eIF4F and lead to translate key oncogenic targets including c-Myc. Interestingly, phosphorylated eIF4E (S209, or p-eIF4E) is dispensable for development or global translation, but required for transformation and optimal tumorigenesis in some models. The underlying causes and significance of elevated p-eIF4E in human cancer and oncogenic translation remains largely unknown. Our novel preliminary data and recent publications supports a critical role of p-eIF4E in human and mouse colon cancer development, and in regulating colon cancer proliferation via ATF4-mediated metabolic and stress adaptation. Pharmacological targeting of eIF4E/4F induces endoplasmic reticulum stress and CRC cell death in culture and in vivo. The central hypothesis of the project is that phosphorylated eIF4E drives colon cancer initiation and progression through ATF4-dependent metabolic and stress reprogramming and serves as an actionable and druggable vulnerability. We will test this hypothesis in three specific Aims. SA1. Define the role of eiF4E phosphorylation in colon cancer development. SA2. Elucidate the mechanisms of p-eIF4E-dependent oncogenesis in colon cancer. SA3. Target eIF4F/4E in colon cancer therapy. The proposed work will develop and employ innovative tools, including phosphorylation defective eIF4E cancer cells and mice, clinical samples, and highly mechanistic and comprehensive approaches to define the role of p-eIF4E in colon cancer biology and therapy. If successful, our work will provide a better understanding of oncogenic translation in protective stress and metabolic adaptation, as well as strategies to target this addiction for therapy. These findings will likely have important implications in treating other cancers with hyperactive Wnt and RAS/RAF for which no effective therapy currently exists.