MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression.
John R P KnightConstantinos AlexandrouGeorge L SkalkaNikola VlahovKathryn A F PennelLeah OfficerAna TeodosioGeorgios KanellosDavid M GaySebastian May-WilsonEwan M SmithArafath K NajumudeenKathryn GilroyRachel A RidgwayDustin J FlanaganLaura McDonaldCraig MacKayAnne CheastyKerri McArthurEmma StanwayJoshua D LeachRene JackstadtJoseph A WaldronAndrew D CampbellGeorgios VlachogiannisNicola ValeriKevin M HaigisNahum SonenbergChristopher G ProudNeil P JonesMartin E SwarbrickHeather J McKinnonWilliam James FallerJohn Le QuesneJoanne EdwardsAnne E WillisMartin BushellOwen James SansomPublished in: Cancer discovery (2020)
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 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 an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.This article is highlighted in the In This Issue feature, p. 995.
Keyphrases
- wild type
- small molecule
- poor prognosis
- endothelial cells
- induced pluripotent stem cells
- small cell lung cancer
- squamous cell carcinoma
- case report
- end stage renal disease
- gene expression
- cancer therapy
- genome wide
- young adults
- papillary thyroid
- oxidative stress
- induced apoptosis
- copy number
- patient reported outcomes
- childhood cancer
- neural network