Combination of Temsirolimus and tyrosine kinase inhibitors in renal carcinoma and endothelial cell lines

Abstract

Multitargeted tyrosine kinase inhibitors (TKIs) (such as Sunitinib and Sorafenib) and mTOR inhibitors (such as Temsirolimus) are effective in treating metastatic clear-cell renal cell carcinoma (CCRCC), by acting on different pathways in both tumour and endothelial cells. A study of their combined effect could be of major interest. We studied endothelial and CCRCC cell lines treated with Sunitinib, Sorafenib, Temsirolimus and 2 drug combinations: Sunitinib-Temsirolimus and Sorafenib-Temsirolimus. We studied inhibition of proliferation with an MTT assay under normoxia and hypoxia, VEGF expression by quantitative RT-PCR and ELISA, and angiogenesis with a Matrigel assay. TKIs and Temsirolimus inhibited proliferation of endothelial and tumour cell lines and inhibited angiogenesis. Anti-proliferative effects were more significant on cell lines with VHL gene inactivation and under hypoxic conditions. VEGF expression was induced by TKIs, but inhibited by Temsirolimus. The Sunitinib/Temsirolimus combination had synergistic or additive effects on the proliferation of tumour and endothelial cell lines. The Sorafenib-Temsirolimus combination had additive effects on the proliferation of most tumour cell lines, but not endothelial cell lines. Both combinations had additive effects on the inhibition of angiogenesis. In our model, Sunitinib, Sorafenib and Temsirolimus had anti-tumour and anti-angiogenic effects. The combinations of Sunitinib or Sorafenib with Temsirolimus had additive or synergistic effects on the inhibition of tumour and endothelial cell proliferation, and on the inhibition of angiogenesis. This work could lead to new trials with lower-dose combinations to prevent side effects and enhance efficacy.