MNK Inhibition Sensitizes <i>KRAS</i> -Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression

<i>KRAS</i>-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in <i>KRAS</i>-mutant colorectal cancer. Using <i>Kras</i>-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRAS^G12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC-dependent cotargeting strategy with remarkable potency in multiple <i>Kras</i>-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application. SIGNIFICANCE: <i>KRAS</i> mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant <i>KRAS</i> modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in <i>KRAS</i>-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.<i>This article is highlighted in the In This Issue feature, p. 995</i>.