Abstract
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 RCC786-0 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. Invivo 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.
Highlights
Renal cell carcinoma (RCC) is the urologic cancer with the highest mortality rate
Sorafenib only partially inhibited the phosphorylation of ERK1/2, which is one of the key intracellular kinases that regulates cell cycle progression, apoptosis resistance, extracellular matrix remodeling, cellular motility, angiogenesis, and drug resistance [12]
These findings suggest that the antitumor effect of sorafenib in RCC could be further improved by combining sorafenib with a MEK inhibitor that abolishes the remaining activity of MEK/ERK
Summary
Renal cell carcinoma (RCC) is the urologic cancer with the highest mortality rate. Approximately one third of patients with RCC exhibit visceral metastasis at the time of diagnosis and approximately 30% of the patients who undergo potentially curative radical nephrectomy develop metastatic disease [1]. The discovery of the molecular links underlying the relationship between Von Hippel-Lindau, hypoxia signaling and VEGF in the biology of clear cell-RCC has led to the development of inhibitors against the VEGF signaling pathway. One of these inhibitors is sorafenib, which inhibits several RTKs including VEGFR-2 and -3, PDGFR-β, the FLT3 and c-KIT receptors [6,7]. The availability of sorafenib is likely to have a considerable clinical impact in RCC, there remains a need for additional treatment options for patients who cannot tolerate full dose sorafenib This need may be covered by one or more of the novel inhibitors or novel combinations currently being developed
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