Sunitinib and pazopanib are anti-angiogenic tyrosine kinase inhibitors (TKIs) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression free and overal 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 which are resistant to sunitinib have a significantly increased angiogenic response compared to tumors which are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared to 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 anti-angiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppresion 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.
Molecular cancer therapeutics. 2015 Oct 20 [Epub ahead of print]
Victoria L Bridgeman, Elaine Wan, Shane Foo, Mark R Nathan, Jonathan C Welti, Sophia Frentzas, Peter B Vermeulen, Natasha Preece, Caroline J Springer, Thomas Powles, Paul D Nathan, James Larkin, Martin Gore, Naveen Vasudev, Andrew R Reynolds
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research. , Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research. , Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research. , Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research. , Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research. , Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research. , Translational Cancer Research Unit, Oncology Center, GZA Hospitals, Saint-Augustinus. , Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research. , Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research. , Experimental Cancer Medicine Centre, Queen Mary University of London. , Medical Oncology, Mount Vernon Cancer Centre. , Medicine, The Royal Marsden Hospital. , Medical Oncology, The Royal Marsden Hospital. , Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research. , Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research