title: 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.
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Sandra Catalina
authors.initials: SC
authors.lastname: Camacho
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Silvers
authors.affiliation: Drug Development Program, Princess Margaret Cancer Center, Toronto, Canada.
authors.forename: Albiruni R A
authors.initials: AR
authors.lastname: Razak
authors.affiliation: Gabrail Cancer Center, Canton, Ohio.
authors.forename: Nashat Y
authors.initials: NY
authors.lastname: Gabrail
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: John F
authors.initials: JF
authors.lastname: Gerecitano
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eva
authors.initials: E
authors.lastname: Kalir
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Elena
authors.initials: E
authors.lastname: Pereira
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Brad R
authors.initials: BR
authors.lastname: Evans
authors.affiliation: School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Nolan
authors.initials: N
authors.lastname: Priedigkeit
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Estefania
authors.initials: E
authors.lastname: Rodriguez
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Michael
authors.initials: M
authors.lastname: Donovan
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Faisal
authors.initials: F
authors.lastname: Khan
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Tamara
authors.initials: T
authors.lastname: Kalir
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Robert
authors.initials: R
authors.lastname: Sebra
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: Uzilov
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Rileen
authors.initials: R
authors.lastname: Sinha
authors.affiliation: Qiagen, Redwood City, California.
authors.forename: Richard
authors.initials: R
authors.lastname: Halpert
authors.affiliation: Qiagen, Redwood City, California.
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Billaud
authors.affiliation: Karyopharm Therapeutics Inc, Natick, Massachusetts.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Karyopharm Therapeutics Inc, Natick, Massachusetts.
authors.forename: Dilara
authors.initials: D
authors.lastname: McCauley
authors.affiliation: Karyopharm Therapeutics Inc, Natick, Massachusetts.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Karyopharm Therapeutics Inc, Natick, Massachusetts.
authors.forename: Tami
authors.initials: T
authors.lastname: Rashal
authors.affiliation: Karyopharm Therapeutics Inc, Natick, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Karyopharm Therapeutics Inc, Natick, Massachusetts.
authors.forename: Mansoor R
authors.initials: MR
authors.lastname: Mirza
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Mau-Sørensen
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Dottino
authors.affiliation: Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York. john.martignetti@mssm.edu.|Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York.|Western Connecticut Health Network, Danbury, Connecticut.
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
mesh_terms: D000179:Acrylates / Q000008:administration & dosage; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010984:Platinum / Q000008:administration & dosage / Q000009:adverse effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics*; D014230:Triazoles / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D000179:Acrylates; D006834:Hydrazines; D028884:Karyopherins; D010984:Platinum; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C576639:KPT-185; C585161:selinexor