Abstract
Abstract Background: Selinexor is a SINE (Selective Inhibitor of Nuclear Export) compound currently in Phase I and II clinical trails for the treatment of hematological and solid malignancies. Selinexor blocks the key nuclear export protein XPO1 to force nuclear retention of tumor suppressor proteins (TSPs), including p53, BRCA1/2, pRB and FOXO3A. Olaparib is an FDA approved therapy for BRCA1/2 mutated ovarian cancer, which inhibits Poly-ADP-Ribose Polymerase (PARP) and prevents DNA damage repair. Furthermore, olaparib is being evaluated for the treatment of Triple Negative Breast Cancer (TNBC). We hypothesized that selinexor would restore genomic surveillance through nuclear accumulation of wild type BRCA1 and therefore combination treatment with olaparib would prevent DNA damage repair to amplify cancer cell death. Methods: The effects of selinexor alone or in combination with olaparib were tested on a panel of 7 TNBC cell lines using MTT and soft-agar colony formation assays in parallel with FACS analysis. In vivo efficacy of single-agent or combination therapy was evaluated using an MDA-MB-468 (BRCA1 wild type, TNBC) xenograft model. Combination index (CI) values were determined using the CompuSyn software and treatment was considered synergistic when CI<1. Results: The median IC50 values for selinexor and olaparib were 1.88 μM (range: 0.27 μM to >10 μM) and 92.6 μM (range: 17.5 μM to >300 μM), respectively. Combination treatment led to synergistic inhibition of proliferation in the 7 TNBC cell lines evaluated. The median CI tested on the panel of cell lines was 0.68 (ranging from 0.4 to 0.96). FACS analysis revealed an additive effect of the selinexor and olaparib combination on S-phase inhibition and G2 arrest in BRCA1 mutated and wild type cells. Furthermore, AnnexinV/PI staining showed an additive effect on TNBC cell apoptosis regardless of BRCA1 mutational status. In the MDA-MB-468 xenograft model, 75% tumor growth inhibition (TGI) was observed in the combination group by day 22 compared to 55% and 35% TGI for single-agent selinexor and olaparib, respectively. Conclusion: Selinexor and olaparib in combination act synergistically to induce apoptosis in TNBC cells and amplify anti-tumor effects in a TNBC xenograft model. These data provide a rationale supporting the study of selinexor/olaparib combination in clinical trials. Citation Format: Helene Marijon, Sigal Gery, Sivan Elloul, Sharon Y. Friedlander, TJ Unger, Robert Carlson, Sharon Shacham, Michael Kauffman, Harold P. Koeffler. Selinexor, a selective inhibitor of nuclear export (SINE) compound, shows enhanced antitumor activity in combination with the PARP inhibitor, olaparib, in 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 LB-255. doi:10.1158/1538-7445.AM2015-LB-255
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