SC144 - a promising small-molecule gp130-inhibitor of IL-6 and Oncostatin-M signaling for treatment of pancreatic cancer

Abstract Background: Interleukin-6 (IL-6), Oncostatin-M (OSM) and the major downstream effector STAT3 are pro-tumorigenic agents in many cancers, including pancreatic ductal adenocarcinoma (PDAC). Glycoprotein 130 (gp130) is a compound of the IL-6 and OSM receptor complex that triggers STAT3 signalling. Recently, a novel small molecule gp130 inhibitor named SC144 was discovered with a broad-spectrum anticancer activity. In this study, we examine the in vitro effects of SC144 in PDAC cell lines and the expression of gp130 in human PDAC specimens.Methods: Growth inhibition by SC144 in human PDAC cell lines AsPC-1 and L3.6pl was assessed using BrdU and MTT assays. Western blotting was performed to identify the inhibitory effect of SC144 on IL-6- or OSM-stimulated STAT3 signaling. Tissue microarrays were constructed from 175 human tumor specimens after pancreatic resection for PDAC. The expression of gp130 in tumor epithelium and tumor stroma was determined by immunohistochemistry. The gp130 expression was then correlated with clinicopathological parameters and survival analysis was performed.Results: SC144 inhibited cell proliferation and viability in human PDAC cells. Treatment with SC144 suppressed IL-6- and OSM-stimulated STAT3Y705 phosphorylation in PDAC cells. gp130 was expressed in epithelium of 78.8% of the tumor samples and in stroma of 9.4% of the tumors. The median overall survival for patients with no epithelial gp130 expression was 15.9 months, whereas for patients with gp130 expression was 16.7 months (p = 0.830). Patients with no stromal gp130 expression showed a poorer survival than patients with stromal gp130 expression in PDAC (median 16.2 and 22.9 months, respectively), but this difference did not reach significance (p = 0.144).Conclusions: SC144 potently inhibits PDAC progression in vitro through binding and inhibition of gp130 and, thereby, causes abrogation of IL-6 or OSM/gp130/STAT3 signaling. Although gp130 is expressed in the epithel of most human PDAC, stromal expression is rare. These results suggest gp130 as a novel drug target and blocking gp130/STAT3 signaling by SC144 as a potential new therapeutical approach for pancreatic cancer.