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dc.contributor.authorKnight, JRP
dc.contributor.authorAlexandrou, C
dc.contributor.authorSkalka, GL
dc.contributor.authorVlahov, N
dc.contributor.authorPennel, K
dc.contributor.authorOfficer, L
dc.contributor.authorTeodosio, A
dc.contributor.authorKanellos, G
dc.contributor.authorGay, DM
dc.contributor.authorMay-Wilson, S
dc.contributor.authorSmith, EM
dc.contributor.authorNajumudeen, AK
dc.contributor.authorGilroy, K
dc.contributor.authorRidgway, RA
dc.contributor.authorFlanagan, DJ
dc.contributor.authorSmith, RCL
dc.contributor.authorMcDonald, L
dc.contributor.authorMacKay, C
dc.contributor.authorCheasty, A
dc.contributor.authorMcArthur, K
dc.contributor.authorStanway, E
dc.contributor.authorLeach, JDG
dc.contributor.authorJackstadt, R
dc.contributor.authorWaldron, JA
dc.contributor.authorCampbell, AD
dc.contributor.authorVlachogiannis, G
dc.contributor.authorValeri, N
dc.contributor.authorHaigis, KM
dc.contributor.authorSonenberg, N
dc.contributor.authorProud, CG
dc.contributor.authorJones, NP
dc.contributor.authorSwarbrick, ME
dc.contributor.authorMcKinnon, HJ
dc.contributor.authorFaller, WJ
dc.contributor.authorLe Quesne, J
dc.contributor.authorEdwards, J
dc.contributor.authorWillis, AE
dc.contributor.authorBushell, M
dc.contributor.authorSansom, OJ
dc.date.accessioned2021-03-03T09:21:32Z
dc.date.available2021-03-03T09:21:32Z
dc.date.issued2020-12-16
dc.identifier.citationCancer discovery, 2020
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4389
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.cd-20-0652
dc.description.abstractKRAS-mutant colorectal cancers (CRC) 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 CRC. 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 CRCs 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 co-targeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population who may benefit from its clinical application.
dc.formatPrint-Electronic
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleMNK inhibition sensitizes KRAS-mutant colorectal cancer to mTORC1 inhibition by reducing eIF4E phosphorylation and c-MYC expression.
dc.typeJournal Article
dcterms.dateAccepted2020-12-11
rioxxterms.versionAM
rioxxterms.versionofrecord10.1158/2159-8290.cd-20-0652
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2020-12-16
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.notesNot 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-statusPublished
pubs.embargo.termsNot known
icr.researchteamGastrointestinal Cancer Biology and Genomics
icr.researchteamGastrointestinal Cancer Biology and Genomicsen_US
dc.contributor.icrauthorValeri, Nicolaen


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