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

Ying Chen; Sandra Catalina Camacho; Thomas R Silvers; Albiruni R A Razak; Nashat Y Gabrail; John F Gerecitano; Eva Kalir; Elena Pereira; Brad R Evans; Susan J Ramus; Fei Huang; Nolan Priedigkeit; Estefania Rodriguez; Michael Donovan; Faisal Khan; Tamara Kalir; Robert Sebra; Andrew Uzilov; Rong Chen; Rileen Sinha; Richard Halpert; Jean-Noel Billaud; Sharon Shacham; Dilara McCauley; Yosef Landesman; Tami Rashal; Michael Kauffman; Mansoor R Mirza; Morten Mau-Sørensen; Peter Dottino; John A Martignetti

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

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

Ying Chen, Sandra Catalina Camacho, Thomas R Silvers, Albiruni R A Razak, Nashat Y Gabrail, John F Gerecitano, Eva Kalir, Elena Pereira, Brad R Evans, Susan J Ramus, Fei Huang, Nolan Priedigkeit, Estefania Rodriguez, Michael Donovan, Faisal Khan, Tamara Kalir, Robert Sebra, Andrew Uzilov, Rong Chen, Rileen SinhaRichard Halpert, Jean-Noel Billaud, Sharon Shacham, Dilara McCauley, Yosef Landesman, Tami Rashal, Michael Kauffman, Mansoor R Mirza, Morten Mau-Sørensen, Peter Dottino, John A Martignetti

68 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Clinical Cancer Research
Vol/bind	23
Udgave nummer	6
Sider (fra-til)	1552-1563
Antal sider	12
ISSN	1078-0432
DOI	https://doi.org/10.1158/1078-0432.CCR-16-1333
Status	Udgivet - 15 mar. 2017

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10.1158/1078-0432.CCR-16-1333

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Chen, Y., Camacho, S. C., Silvers, T. R., Razak, A. R. A., Gabrail, N. Y., Gerecitano, J. F., Kalir, E., Pereira, E., Evans, B. R., Ramus, S. J., Huang, F., Priedigkeit, N., Rodriguez, E., Donovan, M., Khan, F., Kalir, T., Sebra, R., Uzilov, A., Chen, R., ... Martignetti, J. A. (2017). Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer. Clinical Cancer Research, 23(6), 1552-1563. https://doi.org/10.1158/1078-0432.CCR-16-1333

Chen, Y, Camacho, SC, Silvers, TR, Razak, ARA, Gabrail, NY, Gerecitano, JF, Kalir, E, Pereira, E, Evans, BR, Ramus, SJ, Huang, F, Priedigkeit, N, Rodriguez, E, Donovan, M, Khan, F, Kalir, T, Sebra, R, Uzilov, A, Chen, R, Sinha, R, Halpert, R, Billaud, J-N, Shacham, S, McCauley, D, Landesman, Y, Rashal, T, Kauffman, M, Mirza, MR , Mau-Sørensen, M, Dottino, P & Martignetti, JA 2017, 'Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer', Clinical Cancer Research, bind 23, nr. 6, s. 1552-1563. https://doi.org/10.1158/1078-0432.CCR-16-1333

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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. {\textcopyright}2016 AACR.",

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author = "Ying Chen and Camacho, {Sandra Catalina} and Silvers, {Thomas R} and Razak, {Albiruni R A} and Gabrail, {Nashat Y} and Gerecitano, {John F} and Eva Kalir and Elena Pereira and Evans, {Brad R} and Ramus, {Susan J} and Fei Huang and Nolan Priedigkeit and Estefania Rodriguez and Michael Donovan and Faisal Khan and Tamara Kalir and Robert Sebra and Andrew Uzilov and Rong Chen and Rileen Sinha and Richard Halpert and Jean-Noel Billaud and Sharon Shacham and Dilara McCauley and Yosef Landesman and Tami Rashal and Michael Kauffman and Mirza, {Mansoor R} and Morten Mau-S{\o}rensen and Peter Dottino and Martignetti, {John A}",

note = "{\textcopyright}2016 American Association for Cancer Research.",

year = "2017",

month = mar,

day = "15",

doi = "10.1158/1078-0432.CCR-16-1333",

language = "English",

volume = "23",

pages = "1552--1563",

journal = "Clinical Cancer Research",

issn = "1078-0432",

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TY - JOUR

T1 - Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

AU - Chen, Ying

AU - Camacho, Sandra Catalina

AU - Silvers, Thomas R

AU - Razak, Albiruni R A

AU - Gabrail, Nashat Y

AU - Gerecitano, John F

AU - Kalir, Eva

AU - Pereira, Elena

AU - Evans, Brad R

AU - Ramus, Susan J

AU - Huang, Fei

AU - Priedigkeit, Nolan

AU - Rodriguez, Estefania

AU - Donovan, Michael

AU - Khan, Faisal

AU - Kalir, Tamara

AU - Sebra, Robert

AU - Uzilov, Andrew

AU - Chen, Rong

AU - Sinha, Rileen

AU - Halpert, Richard

AU - Billaud, Jean-Noel

AU - Shacham, Sharon

AU - McCauley, Dilara

AU - Landesman, Yosef

AU - Rashal, Tami

AU - Kauffman, Michael

AU - Mirza, Mansoor R

AU - Mau-Sørensen, Morten

AU - Dottino, Peter

AU - Martignetti, John A

PY - 2017/3/15

Y1 - 2017/3/15

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1158/1078-0432.CCR-16-1333

DO - 10.1158/1078-0432.CCR-16-1333

M3 - Journal article

C2 - 27649553

SN - 1078-0432

VL - 23

SP - 1552

EP - 1563

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 6

ER -

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

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