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

作者：John R. P. Knight, Constantinos Alexandrou, George Skalka, Nikola Vlahov, Kathryn A.F. Pennel, Leah Officer, Ana Teodòsio, Georgios Kanellos, David M. Gay, Sebastian May-Wilson, Ewan M. Smith, Arafath K. Najumudeen, Kathryn Gilroy, Rachel A. Ridgway, Dustin J. Flanagan, Rachael C.L. Smith, Laura McDonald, Craig MacKay, Anne Cheasty, Kerri McArthur, Emma Stanway, Joshua D.G. Leach, René Jackstadt, Joseph A. Waldron, Andrew D. Campbell, Georgios Vlachogiannis, Nicola Valeri, Kevin M. Haigis, Nahum Sonenberg, Christopher G. Proud, Neil P. Jones, Martin E. Swarbrick, Heather J. McKinnon, William J. Faller, John Le Quesne, Joanne Edwards, Anne E. Willis, Martin Bushell, Owen J. Sansom · 年份：2023 · DOI：10.1158/2159-8290.c.6549409 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Colorectal Cancer Treatments and Studies、Synthesis and Biological Activity

<div>AbstractKRAS-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 KRAS-mutant colorectal cancer. Using Kras-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 KRASG12D 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 Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application.Significance:KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe...

Data from MNK Inhibition Sensitizes &lt;i&gt;KRAS&lt;/i&gt;-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression

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