Non-canonical IL-6 signaling-mediated activation of YAP regulates cell migration and invasion in ovarian clear cell cancer.

Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL-6 is strongly expressed in OCCA and may therefore provide a novel therapeutic target. Here we use CRISPR/Cas9 and conditional short-hairpin interfering RNA to perform loss-of-function studies in human OCCA cell lines to explore the requirement for IL-6 in vitro and in vivo. While reduction of IL-6 expression exerted limited effects in vitro, its attenuation significantly impaired tumor growth and neovascularization in vivo. In contrast to typical signaling via STAT3, IL-6 in OCCA signaled via a non-canonical pathway involving gp130, Src, and the Hippo pathway protein YAP. A high-throughput combination drug screen identified agents that enhanced cell killing following reduction of IL-6 signaling. Intersection of screen hits obtained from two cell lines and orthogonal approaches to attenuation of IL-6 yielded AKT and EGFR inhibitors as enhancers of the inhibitory monoclonal IL-6 receptor antibody Tocilizumab. This study defines for the first time the requirements for, and mechanisms of, signaling by IL-6 in human OCCA cell lines and identifies potential combinatory therapeutic approaches. Given the molecular diversity of OCCA, further in vitro and in vivo studies are warranted to determine whether such approaches will overcome the limited efficacy of Tocilizumab observed in ovarian cancer to date.