Academic Journal
MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression.
| Τίτλος: | MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression. |
|---|---|
| Συγγραφείς: | Knight, JRP, Alexandrou, C, Skalka, GL, Vlahov, N, Pennel, K, Officer, L, Teodosio, A, Kanellos, G, Gay, DM, May-Wilson, S, Smith, EM, Najumudeen, AK, Gilroy, K, Ridgway, RA, Flanagan, DJ, Smith, RCL, McDonald, L, MacKay, C, Cheasty, A, McArthur, K, Stanway, E, Leach, JD, Jackstadt, R, Waldron, JA, Campbell, AD, Vlachogiannis, G, Valeri, N, Haigis, KM, Sonenberg, N, Proud, CG, Jones, NP, Swarbrick, ME, McKinnon, HJ, Faller, WJ, Le Quesne, J, Edwards, J, Willis, AE, Bushell, M, Sansom, OJ |
| Συνεισφορές: | Valeri, Nicola |
| Στοιχεία εκδότη: | AMER ASSOC CANCER RESEARCH |
| Έτος έκδοσης: | 2021 |
| Συλλογή: | The Institute of Cancer Research (ICR): Publications Repository |
| Περιγραφή: | 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. |
| Τύπος εγγράφου: | article in journal/newspaper |
| Περιγραφή αρχείου: | Print-Electronic; application/pdf |
| Γλώσσα: | English |
| ISSN: | 2159-8290 2159-8274 |
| Relation: | Cancer discovery, 2020; https://repository.icr.ac.uk/handle/internal/4389 |
| Διαθεσιμότητα: | https://repository.icr.ac.uk/handle/internal/4389 |
| Rights: | https://creativecommons.org/licenses/by/4.0 |
| Αριθμός Καταχώρησης: | edsbas.74393C20 |
| Βάση Δεδομένων: | BASE |
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