Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma.
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Date
2016-01-01ICR Author
Author
Bridgeman, VL
Wan, E
Foo, S
Nathan, MR
Welti, JC
Frentzas, S
Vermeulen, PB
Preece, N
Springer, CJ
Powles, T
Nathan, PD
Larkin, J
Gore, M
Vasudev, NS
Reynolds, AR
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cell Line, Tumor
Endothelial Cells
Animals
Humans
Carcinoma, Renal Cell
Kidney Neoplasms
Disease Models, Animal
Neovascularization, Pathologic
Pyridones
Pyrimidinones
Pyrroles
Indoles
Angiogenesis Inhibitors
Protein Kinase Inhibitors
Drug Evaluation, Preclinical
Xenograft Model Antitumor Assays
MAP Kinase Signaling System
Drug Synergism
Drug Resistance, Neoplasm
Female
Von Hippel-Lindau Tumor Suppressor Protein
Sunitinib
Research team
Gene & Oncogene Targeting
Melanoma and Kidney Cancer
Tumour Biology
Translational Immunotherapy
Language
eng
Date accepted
2015-09-17
License start date
2016-01
Citation
Molecular cancer therapeutics, 2016, 15 (1), pp. 172 - 183
Publisher
AMER ASSOC CANCER RESEARCH