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dc.contributor.authorMolina-Arcas, M
dc.contributor.authorMoore, C
dc.contributor.authorRana, S
dc.contributor.authorvan Maldegem, F
dc.contributor.authorMugarza, E
dc.contributor.authorRomero-Clavijo, P
dc.contributor.authorHerbert, E
dc.contributor.authorHorswell, S
dc.contributor.authorLi, L-S
dc.contributor.authorJanes, MR
dc.contributor.authorHancock, DC
dc.contributor.authorDownward, J
dc.date.accessioned2019-09-19T08:54:19Z
dc.date.issued2019-09
dc.identifier.citationScience translational medicine, 2019, 11 (510)
dc.identifier.issn1946-6234
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3352
dc.identifier.eissn1946-6242
dc.identifier.doi10.1126/scitranslmed.aaw7999
dc.description.abstractKRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated protein kinase kinase (MEK) and insulin-like growth factor 1 receptor (IGF1R) signaling. Here, we show that this effect is markedly enhanced by simultaneous inhibition of mammalian target of rapamycin (mTOR) while maintaining selectivity for the KRAS-mutant genotype. Combined mTOR, IGF1R, and MEK inhibition inhibits the principal signaling pathways required for the survival of KRAS-mutant cells and produces marked tumor regression in three different KRAS-driven lung cancer mouse models. Replacing the MEK inhibitor with the mutant-specific KRAS-G12C inhibitor ARS-1620 in these combinations is associated with greater efficacy, specificity, and tolerability. Adding mTOR and IGF1R inhibitors to ARS-1620 greatly improves its effectiveness on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials.
dc.formatPrint
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectAnimals
dc.subjectMice, Nude
dc.subjectCarcinoma, Non-Small-Cell Lung
dc.subjectLung Neoplasms
dc.subjectImidazoles
dc.subjectPyrazines
dc.subjectPyridones
dc.subjectPyrimidinones
dc.subjectMitogen-Activated Protein Kinase Kinases
dc.subjectReceptor, IGF Type 1
dc.subjectRNA, Small Interfering
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectProtein Kinase Inhibitors
dc.subjectSignal Transduction
dc.subjectCell Survival
dc.subjectMutation
dc.subjectProto-Oncogene Proteins p21(ras)
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectTOR Serine-Threonine Kinases
dc.titleDevelopment of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.
dc.typeJournal Article
dcterms.dateAccepted2019-08-09
rioxxterms.versionofrecord10.1126/scitranslmed.aaw7999
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScience translational medicine
pubs.issue510
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Lung Cancer Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Lung Cancer Group
pubs.publication-statusPublished
pubs.volume11en_US
pubs.embargo.termsNot known
icr.researchteamLung Cancer Groupen_US
dc.contributor.icrauthorDownward, Julian David Harryen


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