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

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Constantinos Alexandrou
  • George L. Skalka
  • Nikola Vlahov
  • Kathryn Pennel
  • Leah Officer
  • Ana Teodosio
  • 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. Leach
  • Rene 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


KRAS-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 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 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 an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.

Bibliographical metadata

Original languageEnglish
Pages (from-to)1228-1247
Number of pages20
JournalCancer discovery
Issue number5
Publication statusPublished - 1 May 2021