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To better understand a role of eIF4E S209 in oncogenic translation, we generated  EIF4E S209A/+   heterozygous knockin (4EKI) HCT 116 human colorectal cancer (CRC) cells. 4EKI had little impact on total eIF4E levels, cap binding or global translation, but markedly reduced HCT 116 cell growth in spheroids and mice, and CRC organoid growth. 4EKI strongly inhibited Myc and ATF4 translation, the integrated stress response (ISR)-dependent glutamine metabolic signature, AKT activation and proliferation in vivo. 4EKI inhibited polyposis in  Apc Min/+   mice by suppressing Myc protein and AKT activation. Furthermore, p-eIF4E was highly elevated in CRC precursor lesions in mouse and human. p-eIF4E cooperated with mutant  KRAS  to promote Myc and ISR-dependent glutamine addiction in various CRC cell lines, characterized by increased cell death, transcriptomic heterogeneity and immune suppression upon deprivation. These findings demonstrate a critical role of eIF4E S209-dependent translation in Myc and stress-driven oncogenesis and as a potential therapeutic vulnerability.

eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis