Abstract 1148: Bazedoxifene as a novel GP130 inhibitor for the treatment of triple-negative breast cancer
Authors: Tian Jilai , Cao Yang , Chen Xiang , Xiao Hui , Li Chenglong , Lin Jiayuh 
Published: July 2017

Triple negative breast cancer (TNBC) is the only subtype of breast cancer still lacking effective therapeutic options. Thus, finding novel targets and therapies to treat TNBC is an urgent clinical issue. IL-6 is one of the principal oncogenic mediators in breast cancer and systemic IL-6 levels correlates with poor prognosis, advanced disease, and metastases. Importantly, growth of TNBC cells are replied on autocrine cytokines including IL-6. Therefore, IL-6 signaling represents a novel approach with a potential to improve the therapeutic efficacy. To date, however, no small molecules that target IL-6 signaling are available for clinical cancer therapy. IL-6 binds to IL-6 Rα, then recruits GP130 to form the IL-6/IL-6 Rα/GP130 heterotrimer and triggers a signaling cascade downstream including JAK/STAT3, PI3-K/AKT/mTOR, and MEK/ERK. Therefore, it is possible to target IL-6 signaling by blocking IL-6 binds to GP130 or IL-6 Rα and thus inhibiting its signaling cascade downstream.To effectively target IL-6 signaling, we have utilized a novel drug discovery approach combining Multiple Ligand Simultaneous Docking and drug repurposing to target GP130, since its structure is more druggable than IL-6 Rα. We have identified a FDA-approved drug Bazedoxifene (for the prevention of the postmenopausal osteoporosis in postmenopausal women) with a novel function to inhibit IL-6 and GP130 protein-protein interactions and thus blocking IL-6 signaling cascade downstream. In this study, we examined the therapeutic effect of Bazedoxifene on TNBC, aiming to verify Bazedoxifene as a Novel IL-6/GP130 Inhibitor for TNBC treatments.Our data of western blot showed Bazedoxifene inhibited increased STAT3 phosphorylation induced by IL-6. In addition, Bazedoxifene inhibited phosphorylation of AKT and ERK in TNBC cells that were also produced by IL-6. Furthermore, combination of Bazedoxifene with paclitaxel exhibited more significant inhibition than single agent alone on cell viability in TNBC cells either in 2D or 3D culture model in vitro. Results of colony formation showed that Bazedoxifene could significantly inhibit cell survive and proliferation at 20 μM, which were more effective than Evista and SC144. Moreover, Bazedoxifene could inhibit cell migration. We tested the increased proliferation of TNBC cells using BrdU with the added IL-6, which were then inhibited by Bazedoxifene, demonstrating the Bazedoxifene could achieve a competed inhibition of IL6. The result of significant inhibition of tumor growth in vivo furtherly verified the therapeutic effects of Bazedoxifene. All results showed the significant therapeutic effects of Bazedoxifene in TNBC cells by competed blocking IL6 signaling. Thus, Bazedoxifene holds a great potential for TNBC therapy.

Note: This abstract was not presented at the meeting.

Citation Format: Jilai Tian, Yang Cao, Xiang Chen, Hui Xiao, Chenglong Li, Jiayuh Lin. Bazedoxifene as a novel GP130 inhibitor for the treatment of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1148. doi:10.1158/1538-7445.AM2017-1148