Abstract
Renal cell carcinoma (RCC) is a urologic malignant cancer and often diagnosed at an advanced stage, which results in high mortality. Targeted therapy may improve the quality of life and survival of patients who are not suitable for nephrectomy. Everolimus, an mTOR inhibitor, is currently used as sequential or second-line therapy for RCC refractory to Sunitinib or sorafenib. However, its efficiency is palliative. In this study, we evaluated whether the antitumor activity of everolimus against RCC is enhanced by selumetinib, a selective MEK1 inhibitor. We discovered that everolimus in combination with selumetinib synergistically inhibited the proliferation of Caki-1, 786-O and 769-P cells in vitro. Mechanistically, this combination decreased p-RPS6 and p-4E-BP1 dramatically, which causes G1 cell cycle arrest and prevents reactivation of AKT and ERK. In vivo, the antitumor efficacy and pharmacodynamic biomarkers of the combination therapy were recapitulated in Caki-1 xenograft model. In addition, this combination treatment potently inhibited angiogenesis in xenograft models by impairing VEGF secretion from tumor cells. Our findings provide a sound evidence that combination of everolimus and selumetinib is a potential dual-targeted strategy for renal cell carcinoma.
Highlights
Renal cell carcinoma (RCC) is the most common form of kidney cancer, with an estimated 338,000 new cases diagnosed and 144,000 deaths occurring worldwide every year [1]
The synergistic effects of RAD001 and AZD6244 were reflected by the combination index (CI) calculated by the CompuSyn software according to the Chou-Talalay method [16]
This study discovered two important molecules that restrains the efficacy of everolimus in RCC
Summary
Renal cell carcinoma (RCC) is the most common form of kidney cancer, with an estimated 338,000 new cases diagnosed and 144,000 deaths occurring worldwide every year [1]. Everolimus (RAD001), an oral mTOR inhibitor, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) as a sequential or second-line therapy for advanced RCC refractory to Sunitinib or sorafenib [4]. In a phase 3 trial assessing patients with RCC refractory to EGFR-TKIs, everolimus was shown to slightly improve progression-free survival compared with placebo (median, 4.9 vs 1.9 months) [5]. Combinatorial therapy seems to be potentially more successful in controlling cell signaling [6]. Motzer and colleagues demonstrated a synergistic effect of everolimus and Lenvatinib in patients with advanced or metastatic RCC, and this was the first successful combination therapy approved by FDA [7, 8]. The well-known molecular mechanisms deserve potential probing and combination therapy is promising
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