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Sorafenib, a multikinase inhibitor, is currently used as monotherapy foradvanced renal cell carcinoma (RCC). However, adverse effects associated withits use have been experienced by some patients. In this study, we examined theantitumor and antiangiogenic activities of low-dose sorafenib in combination withthe MEK inhibitor AZD6244 (sorafenib/AZD6244) in a preclinical model of RCC. PrimaryRCC 08-0910 and RCC 786-0 cells as well as patient-derived RCC models were usedto study the antitumor and antiangiogenic activities of sorafenib/AZD6244. Changesof biomarkers relevant to angiogenesis and cell cycle were determined by westernimmunoblotting. Microvessel density, apoptosis and cell proliferation were analyzedby immunohistochemistry. Treatment of RCC 786-0 cells with sorafenib/AZD6244 resultedin G1 cell cycle arrest and blockade of serum-induced cell migration. Sorafenib/AZD6244induced apoptosis in primary RCC 08-0910 cells at low concentrations. In vivoaddition of AZD6244 to sorafenib significantly augmented the antitumor activityof sorafenib and allowed dose reduction of sorafenib without compromising itsantitumor activity. Sorafenib/AZD6244 potently inhibited angiogenesis and phosphorylationof VEGFR-2, PDGFR-β and ERK, p90RSK, p70S6K, cdk-2 and retinoblastoma. Sorafenib/AZD6244also caused upregulation of p27, Bad and Bim but downregulation of survivin andcyclin B1. These resulted in a reduction in cellular proliferation and the inductionof tumor cell apoptosis. Our findings showed that AZD6244 and sorafenib complementeach other to inhibit tumor growth. This study provides sound evidence for theclinical investigation of low-dose sorafenib in combination with AZD6244 in patientswith advanced RCC.

Combination of the ERK inhibitor AZD6244 and low-dose sorafenib in a xenograft model of human renal cell carcinoma