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

被引：76

作者：

Chen, Ying ^{[1
]}

Camacho, Sandra Catalina ^{[1
]}

Silvers, Thomas R. ^{[1
]}

Razak, Albiruni R. A. ^{[2
]}

Gabrail, Nashat Y. ^{[3
]}

Gerecitano, John F. ^{[4
]}

Kalir, Eva

Pereira, Elena ^{[5
]}

Evans, Brad R. ^{[1
]}

Ramus, Susan J. ^{[6
]}

Huang, Fei ^{[1
]}

Priedigkeit, Nolan ^{[1
]}

Rodriguez, Estefania ^{[1
]}

Donovan, Michael ^{[7
]}

Khan, Faisal ^{[7
]}

Kalir, Tamara ^{[7
]}

Sebra, Robert ^{[1
]}

Uzilov, Andrew ^{[1
]}

Chen, Rong ^{[1
]}

Sinha, Rileen ^{[1
]}

Halpert, Richard ^{[8
]}

Billaud, Jean-Noel ^{[8
]}

Shacham, Sharon ^{[9
]}

McCauley, Dilara ^{[9
]}

Landesman, Yosef ^{[9
]}

Rashal, Tami ^{[9
]}

Kauffman, Michael ^{[9
]}

Mirza, Mansoor R. ^{[9
]}

Mau-Sorensen, Morten ^{[10
]}

Dottino, Peter ^{[5
]}

Martignetti, John A. ^{[1
,5
,11
]}

机构：

[1] Icahn Sch Med Mt Sinai, Genet & Genom Sci, New York, NY 10029 USA

[2] Princess Margaret Canc Ctr, Drug Dev Program, Toronto, ON, Canada

[3] Gabrail Canc Ctr, Canton, OH USA

[4] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[5] Icahn Sch Med Mt Sinai, Dept Obstet Gynecol & Reprod Sci, New York, NY 10029 USA

[6] Univ New South Wales, Sch Womens & Childrens Hlth, Sydney, NSW, Australia

[7] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA

[8] Qiagen, Redwood City, CA USA

[9] Karyopharm Therapeut Inc, Natick, MA USA

[10] Rigshosp, Dept Oncol, Copenhagen, Denmark

[11] Western Connecticut Hlth Network, Danbury, CT USA

来源：

CLINICAL CANCER RESEARCH | 2017年 / 23卷 / 06期

关键词：

NF-KAPPA-B; SELECTIVE INHIBITORS; PROTEIN-TRANSPORT; LEPTOMYCIN B; CRM1; SURVIVAL; IDENTIFICATION; APOPTOSIS; KPT-330; SIGNAL;

D O I：

10.1158/1078-0432.CCR-16-1333

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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 selinexortreated 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. (C) 2016 AACR.

引用

页码：1552 / 1563

页数：12

共 51 条

[1]

Ovarian cancer: Strategies for overcoming resistance to chemotherapy [J].

Agarwal, R ;

Kaye, SB .

NATURE REVIEWS CANCER, 2003, 3 (07) :502-516

[2]

Recent insights into the role of NF-κB in ovarian carcinogenesis [J].

Alvero, Ayesha B. .

GENOME MEDICINE, 2010, 2

[3]

OPINION Is NF-κB a good target for cancer therapy? Hopes and pitfalls [J].

Baud, Veronique ;

Karin, Michael .

NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (01) :33-40

[4]

Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[5]

Signaling molecules of the NF-κB pathway shuttle constitutively between cytoplasm and nucleus [J].

Birbach, A ;

Gold, P ;

Binder, BR ;

Hofer, E ;

de Martin, R ;

Schmid, JA .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (13) :10842-10851

[6]

Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method [J].

Chou, Ting-Chao .

CANCER RESEARCH, 2010, 70 (02) :440-446

[7]

The nuclear envelope environment and its cancer connections [J].

Chow, Kin-Hoe ;

Factor, Rachel E. ;

Ullman, Katharine S. .

NATURE REVIEWS CANCER, 2012, 12 (03) :196-209

[8]

KLF6-SV1 Is a Novel Antiapoptotic Protein That Targets the BH3-Only Protein NOXA for Degradation and Whose Inhibition Extends Survival in an Ovarian Cancer Model [J].

DiFeo, Analisa ;

Huang, Fei ;

Sangodkar, Jaya ;

Terzo, Esteban A. ;

Leake, Devin ;

Narla, Goutham ;

Martignetti, John A. .

CANCER RESEARCH, 2009, 69 (11) :4733-4741

[9]

KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia [J].

Etchin, Julia ;

Sanda, Takaomi ;

Mansour, Marc R. ;

Kentsis, Alex ;

Montero, Joan ;

Le, Bonnie T. ;

Christie, Amanda L. ;

McCauley, Dilara ;

Rodig, Scott J. ;

Kauffman, Michael ;

Shacham, Sharon ;

Stone, Richard ;

Letai, Anthony ;

Kung, Andrew L. ;

Look, A. Thomas .

BRITISH JOURNAL OF HAEMATOLOGY, 2013, 161 (01) :117-127

[10]

Mutation of Membrane Type-1 Metalloproteinase, MT1-MMP, Causes the Multicentric Osteolysis and Arthritis Disease Winchester Syndrome [J].

Evans, Brad R. ;

Mosig, Rebecca A. ;

Lobl, Mollie ;

Martignetti, Chiara R. ;

Camacho, Catalina ;

Grum-Tokars, Valerie ;

Glucksman, Marc J. ;

Martignetti, John A. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2012, 91 (03) :572-576

← 1 2 3 4 5 6 →