Abstract 4454: Targeting the gp130 receptor in preclinical models of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with poor clinical outcomes and limited therapeutic options. To date, efforts to implement targetted therapy in TNBC have had limited success. Cumulative evidence suggest that cancer stem cells (CSCs) drive resistance to therapy, tumor recurrence, and may play a determinant role in the aggressive biology of TNBC. Recent studies indicate that CSCs are in reciprocal interaction with tumor microenvironment through cytokine-mediated signaling pathways. IL-6 is emerging as an important mediator of tumor growth and CSC survival. IL-6 is the most studied ligand of the gp130 receptor, which is a potent activator of the JAK/STAT3 signaling pathway important in survival and proliferation. The gp130 receptor is emerging as a promising target for cancer therapy. SC144 is a novel first-in-class gp130 inhibitor that has shown preclinical efficacy in ovarian cancer models. This study explores the effect of gp130 inhibition with SC144 on TNBC preclinical models. Methods: SC144 was provided by Dr. Neamati9s laboratory currently at the University of Michigan. We conducted in vitro studies using well-characterized human BC cell lines with a triple-negative phenotype. The effect of the novel compound SC144 on TNBC cell lines was evaluated using MTT assays for growth inhibition, ALDEFLUOR assay for identification of CSCs, ELISA tests for cytokine levels, and qRT-PCR for gene expression analysis. Results: SC144 inhibits cell growth in the TNBC cell lines SUM159, SUM149, MDAMB231, and HCC38 with IC50 values in a submicromolar range (0.87+0.17 μmol/L, 0.9+0.1 μmol/L, 0.5 μmol/L, 0.4 μmol/L, respectively). In an in vitro culture system of the TNBC cell line SUM159, docetaxel treatment induces a three-fold increase in IL-6 levels by ELISA and increases the CSC population measured by ALDEFLUOR. Pretreatment of SUM159 cells with SC144 significantly sensitized cells to docetaxel. Treatment of SUM159 cells with SC144 in addition to docetaxel significantly reduced the ALDH+ population measured by ALDEFLUOR compared to docetaxel alone (7.79+1% vs 22.23+5%). Investigating the potential effect of SC144 on the CSC population, we found a higher expression level of the IL-6 receptor in ALDH+ cells compared to ALDH- and the bulk population. Furthermore, in SUM159 cells treated with SC144 vs. control for 24 hours we found a significant decrease on expression of genes with documented relevance in CSC maintenance including CD44 (0.08 vs. 0.13), ALDH1a1 (0.001 vs. 0.006), STAT1 (0.004 vs. 0.024) and STAT3 (0.003 vs. 0.014). The in vivo study to test the efficacy of SC144 in a SUM159 xenograft model is undergoing. Conclusions: SC144, a novel gp130 inhibitor, has antitumor activity in human BC cell lines with the triple-negative phenotype. SC144 sensitizes cells to docetaxel therapy, and demonstrates an inhibitory effect on the CSC subpopulation. These findings identify a potential therapeutic target for TNBC. Citation Format: Leonel F. Hernandez-Aya, Yajing Liu, Kelsey Kerr, Shuzo Tamura, Nouri Neamati, Max S. Wicha, Monika L. Burness. Targeting the gp130 receptor in preclinical models of triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4454. doi:10.1158/1538-7445.AM2015-4454