VDX‐111, a novel small molecule, induces necroptosis to inhibit ovarian cancer progression

Abstract

AbstractEpithelial ovarian cancers that are nonhomologous recombination deficient, as well as those that are recurrent and in a platinum‐resistant state, have limited therapeutic options. The objectives of this study were to characterize the mechanism of action and investigate the therapeutic potential of a small molecule, VDX‐111, against ovarian cancer. We examined the ability of VDX‐111 to inhibit the growth of a panel of ovarian cancer cell lines, focusing on BRCA wild‐type lines. We found that VDX‐111 causes a dose‐dependent loss of cell viability across ovarian cancer cell lines. Reverse phase protein array (RPPA) analysis was used to identify changes in cell signaling in response to VDX‐111 treatment. An RPPA analysis performed on cells treated with VDX‐111 detected changes in cell signaling related to autophagy and necroptosis. Immunoblots of OVCAR3 and SNU8 cells confirmed a dose‐dependent increase in LC3A/B and RIPK1. Incucyte live cell imaging was used to measure cell proliferation and death in response to VDX‐111 alone and with inhibitors of apoptosis, necroptosis, and autophagy. Annexin/PI assays suggested predominantly nonapoptotic cell death, while real‐time kinetic imaging of cell growth indicated the necroptosis inhibitor, necrostatin‐1, attenuates VDX‐111‐induced loss of cell viability, suggesting a necroptosis‐dependent mechanism. Furthermore, VDX‐111 inhibited tumor growth in patient‐derived xenograft and syngeneic murine models. In conclusion, the cytotoxic effects of VDX‐111 seen in vitro and in vivo appear to occur in a necroptosis‐dependent manner and may promote an antitumor immune response.