MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression
| Title: | MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression |
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| Authors: | Knight, John R.P.; Alexandrou, Constantinos; Skalka, George L.; Vlahov, Nikola; Pennel, Kathryn; Officer, Leah; Teodosio, Ana; Kanellos, Georgios; Gay, David M.; May-Wilson, Sebastian; Smith, Ewan M.; Najumudeen, Arafath K.; Gilroy, Kathryn; Ridgway, Rachel A.; Flanagan, Dustin J.; Smith, Rachael C.L.; McDonald, Laura; MacKay, Craig; Cheasty, Anne; McArthur, Kerri; Stanway, Emma; Leach, Joshua D.; Jackstadt, Rene; Waldron, Joseph A.; Campbell, Andrew D.; Vlachogiannis, Georgios; Valeri, Nicola; Haigis, Kevin M.; Sonenberg, Nahum; Proud, Christopher G.; Jones, Neil P.; Swarbrick, Martin E.; McKinnon, Heather J.; Faller, William J.; Quesne, John Le; Edwards, Joanne; Willis, Anne E.; Bushell, Martin; Sansom, Owen J. |
| Source: | 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, .... |
| Publication Year: | 2021 |
| Collection: | The University of Manchester: Research Explorer - Publications |
| Subject Terms: | Animals; Colorectal Neoplasms/genetics; Disease Models; Animal; Eukaryotic Initiation Factor-4E/drug effects; Humans; Intracellular Signaling Peptides and Proteins/drug effects; MTOR Inhibitors/pharmacology; Mice; Inbred C57BL; Phosphorylation; Protein Serine-Threonine Kinases/drug effects; ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre |
| Description: | 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. |
| Document Type: | article in journal/newspaper |
| Language: | English |
| ISSN: | 2159-8274; 2159-8290 |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/33328217; info:eu-repo/semantics/altIdentifier/pissn/2159-8274; info:eu-repo/semantics/altIdentifier/eissn/2159-8290 |
| DOI: | 10.1158/2159-8290.CD-20-0652 |
| Availability: | https://research.manchester.ac.uk/en/publications/e2b9afde-dfcb-40fe-b3a3-ece044a73148; https://doi.org/10.1158/2159-8290.CD-20-0652 |
| Rights: | info:eu-repo/semantics/openAccess |
| Accession Number: | edsbas.223EE4CE |
| Database: | BASE |