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

Abstract

&lt;div&gt;Abstract&lt;p&gt;&lt;i&gt;KRAS&lt;/i&gt;-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 &lt;i&gt;KRAS&lt;/i&gt;-mutant colorectal cancer. Using &lt;i&gt;Kras&lt;/i&gt;-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&lt;sup&gt;G12D&lt;/sup&gt; 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 &lt;i&gt;Kras&lt;/i&gt;-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application.&lt;/p&gt;Significance:&lt;p&gt;&lt;i&gt;KRAS&lt;/i&gt; mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant &lt;i&gt;KRAS&lt;/i&gt; modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in &lt;i&gt;KRAS&lt;/i&gt;-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.&lt;/p&gt;&lt;p&gt;&lt;i&gt;This article is highlighted in the In This Issue feature, p. 995&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;