Interleukin-6 induces drug resistance in renal cell carcinoma

Abstract

Metastatic renal cell carcinoma (mRCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKIs), the novel targeted agents have been used for the treatment of mRCC and have shown efficacy. Interferon (IFN)-α is also one of the most frequently used agents in immunotherapy. However, drug resistance needs to be overcome to achieve a sufficiently positive effect. Interleukin-6 (IL-6), which induce suppressor of cytokine signaling-3 (SOCS3) expression, is one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). To analyze the influence of IL-6 in drug resistance of RCC, anti-IL-6 receptor antibody was used in combination with IFN or TKIs. The SOCS3 mRNA expression level was significantly increased by IFNα stimulation in 786-O RCC cells which were resistant to IFN, but not in ACHN cells that were sensitive to IFN. The overexpression of SOCS3 by gene transfection in ACHN significantly inhibited the growthinhibitory effect of IFNα. An in vivo study demonstrated that coadministration of SOCS3-targeted siRNA promoted INFαinduced cell death and growth suppression in 786-O cell xenograft. SOCS3 could be a key component in the resistance to interferon treatment of renal cell carcinoma. Because SOCS3 is rapidly upregulated by IL-6 and a negative regulator of cytokine signaling, IL-6 expression on RCC cells was also analyzed and the 786-O cells showed the high level of IL-6 mRNA expression under the condition of interferon stimulation. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells by interferon stimulation accompanied with phosphorylation of STAT1 and inhibited SOCS3 expression. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumor growth in a xenograft model. We also hypothesized that TKI resistance and IL-6 secretion are causally connected. And we found that 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. A combination therapy with tocilizumab and TKI suppresses 786-O tumor growth and inhibits angiogenesis in vivo more efficient than TKI alone. Our findings suggest that IL-6 could induce drug resistance on RCC, and combination therapy of IL-6R inhibitors and IFN/TKIs may represent a novel therapeutic approach for RCC treatment.

Targeting STAT3 in Cancer Immunotherapy

“…In contrast, STAT3 becomes hyperactivated in the majority of human cancers and is generally associated with poor clinical prognosis [ 8 ]. Therefore, it is not surprising that STAT3 signaling pathway has long been recognized as a potential therapeutic target for cancer therapy owing to their roles in tumor formation, metastasis and drug resistance [ 9 – 12 ]. Moreover, accumulating evidence reveals that STAT3 hyperactivation can mediate tumor-induced immunosuppression at many levels [ 13 , 14 ].…”

Identification of miRNA signatures for kidney renal clear cell carcinoma using the tensor-decomposition method

“…In fact, IL-6 is a potential target in cancer therapy [41,42]. Ishibashi et al reported that IL-6 suppresses the expression of the cytokine signaling-3 (SOCS3) gene and is associated with poor prognosis of kidney cancer patients [43]. Next, we checked if the selected miRNAs and mRNAs were common between the TCGA and GEO datasets.…”

Drug repurposing against COVID-19: focus on anticancer agents

“…This compound is a humanized monoclonal antibody (MoAb) targeting interleukin-6 receptor (IL-6R). Pharmacology, pharmacokinetics, clinical efficacy, safety, and role of tocilizumab in rheumatoid arthritis (RA) are well-established [58] and possibly due also to its effect on the AKT/mTOR pathway [59]. Tocilizumab has also been approved for the treatment of the cytokine storm associated with cancer immunotherapy [60] or, more often, with CAR-T therapy [61,62].…”