The combination of the NT157 and sorafenib as a new therapeutic option for hepatocellular carcinoma.

Abstract

e15610 Background: Sorafenib, which was the only choice of systemic therapy in the past ten years in HCC. But sorafenib alone achieves limited efficacy. Reversing sorafenib resistance was difficulty for oncologist. Based on previous study, we investigated whether NT157 augmented antitumor activity of sorafenib and underlying mechanisms. Methods: HCC cell lines and xenografts were employed to determine antitumor activity of NT157 combined with sorafenib and explore underlying mechanisms. Results: NT157 inhibited proliferation and induced apoptosis in dose and time dependent manner in HCC cells. HCC tumor was efficiently inhibited by NT157 in vivo. Mechanistic investigations elucidated NT157 induced phosphorylation of IRS1 by ERK pathway, and blockade of Stat3 pathway was independent of ERK pathways. NT157-activated p-ERK committed them to degradation by proteasome. CCL20 and CXCL8 were selected as efficacy markers by sequence, which effectively and minimal invasively predict efficacy. No major toxicity of liver, kidney and hemogram was observed, but SII (systemic immune-inflammation = N*P/L) was much lower, implying NT157 may influence immune and inflammatory reaction. Combination of NT157 and sorafenib increased percentage of apoptotic cells, c-caspase3 and PARP. Besides, sorafenib can reverse transient elevation of p-ERK by NT157, which may be potential mechanism of two drugs performing synergy. In vivo tumor volume and weight decreased in combination group compared with monotherapy. NT157 decreased p-AKT, which was overexpressed in resistant cell, implying NT157 may reverse sorafenib resistance by inhibiting AKT. To explore mechanism of sorafenib resistance in HCC, we established sorafenib-resistant HCC cell. Combination of two drugs inhibited cell viability, increased the percentage of apoptotic cells and activated of caspase3 and PARP cleavage in resistant cell. Conclusions: Our findings demonstrate NT157 displays potent antitumor effect in HCC via blockade IRS1 and STAT3 pathways. Combination of NT157 and sorafenib has potential therapeutic effect, even in sorafenib-resistant HCC cell. These findings identify a novel therapeutic strategy for HCC using a combination of NT157 and sorafenib.