Supplementary Figure 1. Overview of XPO1's role in nuclear:cytoplasmic transport. Supplementary Figure 2. KPT-185 is much less toxic to patient-derived benign cells than patient-derived serous high grade OvCa cells. Supplementary Figure 3. FACS cell cycle analysis of indicated cell lines treated with KPT-185 at respective IC50 doses or control DMSO for 36 hours. Data shown as mean percentage in G1 phase. Supplementary Figure 4. Combinatorial effects of KPT-185 and cisplatin in OvCa cells. Supplementary Figure 5. Knockdown of p53 by p53 siRNA blocked the KPT-mediated apoptosis in CP70 cells. Supplementary Figure 6. P53 network following KPT-185 treatment in CP70 cells. Supplementary Figure7. Representative images and mutation status of original human tumor pathology specimens and paired PDX tumor sections.
ARTICLE ABSTRACT
Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer.Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor.Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor–mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all.Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer. Clin Cancer Res; 23(6); 1552–63. ©2016 AACR.
