Abstract P3-07-01: Selinexor, a selective inhibitor of nuclear export, demonstrates efficacy in preclinical models of triple negative breast cancer

Abstract

Abstract Background: Approximately 15% of all breast cancers are categorized as triple negative (TNBC) for which the only chemotherapy is known to be effective, yet often fails to achieve remission. Nuclear exporter XPO1 (Exportin1 or CRM1) is a promising target for cancer therapy that mediates the transport of multiple tumor suppressors and cell cycle regulators that have been known to be relevant predictors in the mechanism and severity of TNBC. Given the pressing need for novel therapies for this disease, we sought to determine the antitumor effects of selinexor, a novel inhibitor of nuclear export, on triple negative breast cancers in vitro and in vivo as well as to address its mechanism of action. Methods: 26 breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro. Using cell proliferation assays the half maximal inhibitory concentration (IC50) was calculated using isobologram curves after 3 days of treatment; sensitivity was defined as IC50 <1000nM. We then assessed mechanistic effects on apoptosis and cell proliferation using flow cytometry analysis with annexin V and propidium iodide and using western blot analysis we also studied its effects on markers of inhibition of apoptosis. In vivo efficacy was studied as single agent and in combination with standard chemotherapy agents in TNBC patient derived xenografts (PDXs) with varying levels of sensitivity to chemotherapy as well as with varying statuses of TP53 and PIK3CA, and gene expression subtypes. Results: Selinexor demonstrated growth inhibition in all fourteen TNBC cell lines tested; TNBC cell lines were more sensitive to selinexor (median IC50 44nM, range 11 - 550nM), compared to ER+ cells lines (median IC50 of 13000 nM, range of 40nM - > 1000 nM; P=0.017). Treatment with selinexor decreased expression levels of XPO1, as well as survivin and XIAP, and induced apoptosis. In multiple TNBC cell lines selinexor was synergistic with paclitaxel, carboplatin, eribulin and doxorubicin in vitro (median combination index 0.6, range 0.5-0.8). Selinexor as a single agent reduced tumor growth in vivo in 4 of 5 different TNBC PDX models with a median tumor growth inhibition ratio score (T/C) of 48% (range 34-59%) and demonstrated greater antitumor efficacy in combination with paclitaxel or eribulin with an average T/C score of 27% and 12% respectively. Conclusions: Selinexor is a promising therapeutic agent for triple negative breast cancer and it has potential as a combination agent with standard chemotherapy. Citation Format: Paez Arango N, Evans KW, Zhao M, Yuca E, Scott SM, Janku F, Ueno NT, Tripathy D, Kim C, Naing A, Funda M-B. Selinexor, a selective inhibitor of nuclear export, demonstrates efficacy in preclinical models of triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-01.