Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer.

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.

DOI: 10.1158/1078-0432.CCR-16-1333

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@article{Chen2017InhibitionOT, title={Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer.}, author={Ying Chen and Sandra Catalina Camacho and Thomas R Silvers and Albiruni Ryan Abdul Razak and Nashat Y Gabrail and John F. Gerecitano and Eva Kalir and Elena Pereira and Brad R Evans and Susan J Ramus and Fei Huang and Nolan Michael Priedigkeit and Estefan{\'i}a Rodr{\'i}guez and Michael J. Donovan and Faisal M. Khan and Tamara L Kalir and Robert P. Sebra and Andrew V. Uzilov and Rong Chen and Rileen Sinha and Richard L. Halpert and Jean-Noel Billaud and Sharon Shacham and Dilara McCauley and Yosef Landesman and Tami Rashal and Michael G. Kauffman and Mansoor Mirza and Morten Mau-S\orensen and Peter R Dottino and John A. Martignetti}, journal={Clinical cancer research : an official journal of the American Association for Cancer Research}, year={2017}, volume={23 6}, pages={1552-1563} }