dc.contributor.author | Molina-Arcas, M | |
dc.contributor.author | Moore, C | |
dc.contributor.author | Rana, S | |
dc.contributor.author | van Maldegem, F | |
dc.contributor.author | Mugarza, E | |
dc.contributor.author | Romero-Clavijo, P | |
dc.contributor.author | Herbert, E | |
dc.contributor.author | Horswell, S | |
dc.contributor.author | Li, L-S | |
dc.contributor.author | Janes, MR | |
dc.contributor.author | Hancock, DC | |
dc.contributor.author | Downward, J | |
dc.date.accessioned | 2019-09-19T08:54:19Z | |
dc.date.issued | 2019-09 | |
dc.identifier.citation | Science translational medicine, 2019, 11 (510) | |
dc.identifier.issn | 1946-6234 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3352 | |
dc.identifier.eissn | 1946-6242 | |
dc.identifier.doi | 10.1126/scitranslmed.aaw7999 | |
dc.description.abstract | KRAS 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.format | Print | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Animals | |
dc.subject | Mice, Nude | |
dc.subject | Carcinoma, Non-Small-Cell Lung | |
dc.subject | Lung Neoplasms | |
dc.subject | Imidazoles | |
dc.subject | Pyrazines | |
dc.subject | Pyridones | |
dc.subject | Pyrimidinones | |
dc.subject | Mitogen-Activated Protein Kinase Kinases | |
dc.subject | Receptor, IGF Type 1 | |
dc.subject | RNA, Small Interfering | |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Signal Transduction | |
dc.subject | Cell Survival | |
dc.subject | Mutation | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | Proto-Oncogene Proteins c-akt | |
dc.subject | Phosphatidylinositol 3-Kinases | |
dc.subject | TOR Serine-Threonine Kinases | |
dc.title | Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-08-09 | |
rioxxterms.versionofrecord | 10.1126/scitranslmed.aaw7999 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Science translational medicine | |
pubs.issue | 510 | |
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/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-status | Published | |
pubs.volume | 11 | en_US |
pubs.embargo.terms | Not known | |
icr.researchteam | Lung Cancer Group | en_US |
dc.contributor.icrauthor | Downward, Julian David Harry | |