MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression
| Autor: | Anne E. Willis, Laura McDonald, George Skalka, Andrew D. Campbell, Heather McKinnon, Kevin M. Haigis, John R. P. Knight, Sebastian May-Wilson, Kathryn Gilroy, William J. Faller, Emma Stanway, Leah Officer, Rachael C. L. Smith, Joshua D.G. Leach, Joseph A. Waldron, Rachel A. Ridgway, Nicola Valeri, Ewan M. Smith, Arafath Kaja Najumudeen, Nahum Sonenberg, Joanne Edwards, Rene Jackstadt, Ana Teodósio, John Le Quesne, Dustin J. Flanagan, Anne Cheasty, Georgios Kanellos, Kerri McArthur, Christopher G. Proud, Constantinos Alexandrou, Georgios Vlachogiannis, Neil P. Jones, Nikola Vlahov, Owen J. Sansom, Kathryn Af Pennel, Craig MacKay, Martin E. Swarbrick, Martin Bushell |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Eukaryotic Initiation Factor-4E/drug effects Colorectal cancer Mutant mTORC1 Biology medicine.disease_cause 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Humans Protein Serine-Threonine Kinases/drug effects Phosphorylation neoplasms Intracellular Signaling Peptides and Proteins/drug effects MTOR Inhibitors/pharmacology Mutation Manchester Cancer Research Centre ResearchInstitutes_Networks_Beacons/mcrc EIF4E Translation (biology) medicine.disease Colorectal Neoplasms/genetics digestive system diseases 3. Good health Mice Inbred C57BL Disease Models Animal 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research KRAS |
| Zdroj: | Knight, J R P, Alexandrou, C, Skalka, G L, Vlahov, N, Pennel, K, Officer, L, Teodosio, A, Kanellos, G, Gay, D M, May-Wilson, S, Smith, E M, Najumudeen, A K, Gilroy, K, Ridgway, R A, Flanagan, D J, Smith, R C L, McDonald, L, MacKay, C, Cheasty, A, McArthur, K, Stanway, E, Leach, J D, Jackstadt, R, Waldron, J A, Campbell, A D, Vlachogiannis, G, Valeri, N, Haigis, K M, Sonenberg, N, Proud, C G, Jones, N P, Swarbrick, M E, McKinnon, H J, Faller, W J, Quesne, J L, Edwards, J, Willis, A E, Bushell, M & Sansom, O J 2021, ' MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression ', Cancer discovery, vol. 11, no. 5, pp. 1228-1247 . https://doi.org/10.1158/2159-8290.CD-20-0652 |
| ISSN: | 2159-8274 |
| DOI: | 10.1158/2159-8290.CD-20-0652 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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