Abstract
Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens. Cell proliferation and signal transduction activity were then quantified after co-treatment with tocilizumab, an IL-6R inhibitor, in vitro and in vivo. 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. Using a mouse xenograft model we can show that a combination therapy with tocilizumab and low dosage of sorafenib suppresses 786-O tumor growth, reduces AKT-mTOR pathway and inhibits angiogenesis in vivo more efficient than sorafenib alone. Furthermore FDG-PET imaging detected early decrease of maximum standardized uptake values prior to extended central necrosis.Our findings suggest that a combination therapy of IL-6R inhibitors and TKIs may represent a novel therapeutic approach for RCC treatment.
Highlights
Renal cell carcinomas (RCC) account for about 85 percent of renal cancers and a quarter of the patients present with advanced disease, including locally invasive or metastatic renal cell carcinoma [1]
To find out if the enhanced secretion of IL-6 and vascular endothelial growth factor (VEGF) proteins in 786-O cells corresponds to an enhanced mRNA level of the respective genes, we investigated the influence of Tyrosine kinase inhibitors (TKI) on IL-6 and VEGF expression
The present study demonstrates that low concentration TKI treatment induces IL-6 and VEGF expression and secretion only in 786-O cells, whereas other RCC cell lines were not affected by TKI concerning cytokine secretion
Summary
Renal cell carcinomas (RCC) account for about 85 percent of renal cancers and a quarter of the patients present with advanced disease, including locally invasive or metastatic renal cell carcinoma [1]. Alternative signaling pathway activation has been shown to be responsible for this resistance for most of the listed targeted RCC therapies. According to these studies, one of the central effects involved in TKI resistance [10] is probably due to sphingosine kinase-1 (SK1) activation, that stabilizes HIF-1α via enhanced AKT and ERK signaling [11]. One of the central effects involved in TKI resistance [10] is probably due to sphingosine kinase-1 (SK1) activation, that stabilizes HIF-1α via enhanced AKT and ERK signaling [11] To date it is not clear which mechanisms lead to these enhanced signaling activities. IL-6-induced activation of AKT is involved in protection against apoptosis, as well as in enhanced proliferation in some cancer cells [15,16,17]
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