Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma.
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.
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research (ICR), London, United Kingdom.
Victoria L
VL
Bridgeman
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research (ICR), London, United Kingdom. The Royal Marsden (RM), London, United Kingdom.
Elaine
E
Wan
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research (ICR), London, United Kingdom.
Shane
S
Foo
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research (ICR), London, United Kingdom.
Mark R
MR
Nathan
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research (ICR), London, United Kingdom.
Jonathan C
JC
Welti
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research (ICR), London, United Kingdom. The Royal Marsden (RM), London, United Kingdom.
Sophia
S
Frentzas
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research (ICR), London, United Kingdom. Translational Cancer Research Unit, GZA Hospitals St. Augustinus, Antwerp, Belgium.
Peter B
PB
Vermeulen
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
Natasha
N
Preece
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom.
Caroline J
CJ
Springer
Experimental Cancer Medicine Centre, Queen Mary University of London, London, United Kingdom.
Thomas
T
Powles
Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, United Kingdom.
Paul D
PD
Nathan
The Royal Marsden (RM), London, United Kingdom.
James
J
Larkin
The Royal Marsden (RM), London, United Kingdom.
Martin
M
Gore
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research (ICR), London, United Kingdom. The Royal Marsden (RM), London, United Kingdom. andrew.reynolds@icr.ac.uk N.Vasudev@leeds.ac.uk.
Naveen S
NS
Vasudev
Tumour Biology Team, The Breast Cancer Now Toby Robins Research Centre, Mary-Jean Mitchell Green Building, The Institute of Cancer Research (ICR), London, United Kingdom. andrew.reynolds@icr.ac.uk N.Vasudev@leeds.ac.uk.
Andrew R
AR
Reynolds
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D000077210:Sunitinib; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D011758:Pyrroles; C560077:trametinib; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000077210:Sunitinib