dc.contributor.author | Bridgeman, VL | |
dc.contributor.author | Wan, E | |
dc.contributor.author | Foo, S | |
dc.contributor.author | Nathan, MR | |
dc.contributor.author | Welti, JC | |
dc.contributor.author | Frentzas, S | |
dc.contributor.author | Vermeulen, PB | |
dc.contributor.author | Preece, N | |
dc.contributor.author | Springer, CJ | |
dc.contributor.author | Powles, T | |
dc.contributor.author | Nathan, PD | |
dc.contributor.author | Larkin, J | |
dc.contributor.author | Gore, M | |
dc.contributor.author | Vasudev, NS | |
dc.contributor.author | Reynolds, AR | |
dc.date.accessioned | 2018-07-05T11:10:45Z | |
dc.date.issued | 2016-01-01 | |
dc.identifier.citation | Molecular cancer therapeutics, 2016, 15 (1), pp. 172 - 183 | |
dc.identifier.issn | 1535-7163 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/1997 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.doi | 10.1158/1535-7163.mct-15-0170 | |
dc.description.abstract | Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC. | |
dc.format | Print-Electronic | |
dc.format.extent | 172 - 183 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Endothelial Cells | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Carcinoma, Renal Cell | |
dc.subject | Kidney Neoplasms | |
dc.subject | Disease Models, Animal | |
dc.subject | Neovascularization, Pathologic | |
dc.subject | Pyridones | |
dc.subject | Pyrimidinones | |
dc.subject | Pyrroles | |
dc.subject | Indoles | |
dc.subject | Angiogenesis Inhibitors | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Drug Evaluation, Preclinical | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | MAP Kinase Signaling System | |
dc.subject | Drug Synergism | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Female | |
dc.subject | Von Hippel-Lindau Tumor Suppressor Protein | |
dc.subject | Sunitinib | |
dc.title | Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2015-09-17 | |
rioxxterms.versionofrecord | 10.1158/1535-7163.mct-15-0170 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2016-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Molecular cancer therapeutics | |
pubs.issue | 1 | |
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 Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Gene & Oncogene Targeting | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer/Melanoma and Kidney Cancer (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Tumour Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
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 Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Gene & Oncogene Targeting | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer/Melanoma and Kidney Cancer (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Tumour Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 15 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene & Oncogene Targeting | |
icr.researchteam | Melanoma and Kidney Cancer | |
icr.researchteam | Tumour Biology | |
icr.researchteam | Translational Immunotherapy | |
dc.contributor.icrauthor | Bridgeman, Victoria | |
dc.contributor.icrauthor | Foo, Shane | |
dc.contributor.icrauthor | Nathan, Mark | |
dc.contributor.icrauthor | Preece, Natasha | |
dc.contributor.icrauthor | Springer, Caroline | |
dc.contributor.icrauthor | Reynolds, Andrew | |