Combination of the ERK inhibitor AZD6244 and low-dose sorafenib in a             xenograft model of human renal cell carcinoma.
Sorafenib, a multikinase inhibitor, is currently used as monotherapy for             advanced renal cell carcinoma (RCC). However, adverse effects associated with             its use have been experienced by some patients. In this study, we examined the             antitumor and antiangiogenic activities of low-dose sorafenib in combination with             the MEK inhibitor AZD6244 (sorafenib/AZD6244) in a preclinical model of RCC. Primary             RCC 08-0910 and RCC 786-0 cells as well as patient-derived RCC models were used             to study the antitumor and antiangiogenic activities of sorafenib/AZD6244. Changes             of biomarkers relevant to angiogenesis and cell cycle were determined by western             immunoblotting. Microvessel density, apoptosis and cell proliferation were analyzed             by immunohistochemistry. Treatment of RCC 786-0 cells with sorafenib/AZD6244 resulted             in G1 cell cycle arrest and blockade of serum-induced cell migration. Sorafenib/AZD6244             induced apoptosis in primary RCC 08-0910 cells at low concentrations. In vivo             addition of AZD6244 to sorafenib significantly augmented the antitumor activity             of sorafenib and allowed dose reduction of sorafenib without compromising its             antitumor activity. Sorafenib/AZD6244 potently inhibited angiogenesis and phosphorylation             of VEGFR-2, PDGFR-β and ERK, p90RSK, p70S6K, cdk-2 and retinoblastoma. Sorafenib/AZD6244             also caused upregulation of p27, Bad and Bim but downregulation of survivin and             cyclin B1. These resulted in a reduction in cellular proliferation and the induction             of tumor cell apoptosis. Our findings showed that AZD6244 and sorafenib complement             each other to inhibit tumor growth. This study provides sound evidence for the             clinical investigation of low-dose sorafenib in combination with AZD6244 in patients             with advanced RCC.
Department of Urology, Singapore General Hospital, Singapore,                     Republic of Singapore.
John Shyi Peng
JS
Yuen
Mei Yi
MY
Sim
Hong Gee
HG
Sim
Tsung Wen
TW
Chong
Weber Kam On
WK
Lau
Christopher Wai Sam
CW
Cheng
Richard Weijie
RW
Ong
Hung
H
Huynh
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage; D001562:Benzimidazoles / Q000008:administration & dosage; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D000077157:Sorafenib; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
C517975:AZD 6244; D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; D001562:Benzimidazoles; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2; D048052:Mitogen-Activated Protein Kinase 3