dc.contributor.author | Knight, JRP | |
dc.contributor.author | Alexandrou, C | |
dc.contributor.author | Skalka, GL | |
dc.contributor.author | Vlahov, N | |
dc.contributor.author | Pennel, K | |
dc.contributor.author | Officer, L | |
dc.contributor.author | Teodosio, A | |
dc.contributor.author | Kanellos, G | |
dc.contributor.author | Gay, DM | |
dc.contributor.author | May-Wilson, S | |
dc.contributor.author | Smith, EM | |
dc.contributor.author | Najumudeen, AK | |
dc.contributor.author | Gilroy, K | |
dc.contributor.author | Ridgway, RA | |
dc.contributor.author | Flanagan, DJ | |
dc.contributor.author | Smith, RCL | |
dc.contributor.author | McDonald, L | |
dc.contributor.author | MacKay, C | |
dc.contributor.author | Cheasty, A | |
dc.contributor.author | McArthur, K | |
dc.contributor.author | Stanway, E | |
dc.contributor.author | Leach, JD | |
dc.contributor.author | Jackstadt, R | |
dc.contributor.author | Waldron, JA | |
dc.contributor.author | Campbell, AD | |
dc.contributor.author | Vlachogiannis, G | |
dc.contributor.author | Valeri, N | |
dc.contributor.author | Haigis, KM | |
dc.contributor.author | Sonenberg, N | |
dc.contributor.author | Proud, CG | |
dc.contributor.author | Jones, NP | |
dc.contributor.author | Swarbrick, ME | |
dc.contributor.author | McKinnon, HJ | |
dc.contributor.author | Faller, WJ | |
dc.contributor.author | Le Quesne, J | |
dc.contributor.author | Edwards, J | |
dc.contributor.author | Willis, AE | |
dc.contributor.author | Bushell, M | |
dc.contributor.author | Sansom, OJ | |
dc.date.accessioned | 2021-03-03T09:21:32Z | |
dc.date.available | 2021-03-03T09:21:32Z | |
dc.date.issued | 2021-05-01 | |
dc.identifier.citation | Cancer discovery, 2020 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4389 | |
dc.identifier.eissn | 2159-8290 | |
dc.identifier.doi | 10.1158/2159-8290.cd-20-0652 | |
dc.description.abstract | 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. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-12-11 | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1158/2159-8290.cd-20-0652 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-12-16 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer discovery | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gastrointestinal Cancer Biology and Genomics | |
pubs.publication-status | Published | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gastrointestinal Cancer Biology and Genomics | |
icr.researchteam | Gastrointestinal Cancer Biology and Genomics | |
dc.contributor.icrauthor | Valeri, Nicola | |