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

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.

[1]  R. Carlson,et al.  First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  A. Sood,et al.  XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A , 2015, Clinical Cancer Research.

[3]  E. Baloglu,et al.  Clinical translation of nuclear export inhibitors in cancer. , 2014, Seminars in cancer biology.

[4]  H. P. Koeffler,et al.  KPT-330 has antitumour activity against non-small cell lung cancer , 2014, British Journal of Cancer.

[5]  A. Razak,et al.  Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy. , 2014, Cancer discovery.

[6]  J. Sarkaria,et al.  Tumorgrafts as In Vivo Surrogates for Women with Ovarian Cancer , 2014, Clinical Cancer Research.

[7]  R. Weiss,et al.  CRM1 blockade by selective inhibitors of nuclear export attenuates kidney cancer growth. , 2013, The Journal of urology.

[8]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[9]  A. Letai,et al.  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 , 2013, British journal of haematology.

[10]  Yazmin P. Carrasco,et al.  Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1 , 2013, Proceedings of the National Academy of Sciences.

[11]  A. Jemal,et al.  Cancer statistics, 2013 , 2013, CA: a cancer journal for clinicians.

[12]  Michael L. Wang,et al.  Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma. , 2013, Experimental hematology.

[13]  Henning Urlaub,et al.  Identification of CRM1-dependent Nuclear Export Cargos Using Quantitative Mass Spectrometry* , 2012, Molecular & Cellular Proteomics.

[14]  S. Wagner,et al.  Inhibition of CRM1-mediated nucleocytoplasmic transport: triggering human melanoma cell apoptosis by perturbing multiple cellular pathways. , 2012, The Journal of investigative dermatology.

[15]  Yuh Min Chook,et al.  Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. , 2012, Blood.

[16]  M. D'Angelo,et al.  Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions , 2012, Nature Reviews Molecular Cell Biology.

[17]  N. Grishin,et al.  NESdb: a database of NES-containing CRM1 cargoes , 2012, Molecular biology of the cell.

[18]  Rebecca A Mosig,et al.  Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome. , 2012, American journal of human genetics.

[19]  Y. Yoneda,et al.  Intrinsic and extrinsic negative regulators of nuclear protein transport processes , 2012, Genes to cells : devoted to molecular & cellular mechanisms.

[20]  D. Sullivan,et al.  Nuclear export of proteins and drug resistance in cancer. , 2012, Biochemical pharmacology.

[21]  Z. Szallasi,et al.  Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. , 2012, Endocrine-related cancer.

[22]  Rachel E. Factor,et al.  The nuclear envelope environment and its cancer connections , 2012, Nature Reviews Cancer.

[23]  Chris Albanese,et al.  ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. , 2012, The American journal of pathology.

[24]  Karl Gademann,et al.  Controlling protein transport by small molecules. , 2011, Current drug targets.

[25]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[26]  J. Martignetti,et al.  Nucleo-Cytoplasmic Localization Domains Regulate Krüppel-Like Factor 6 (KLF6) Protein Stability and Tumor Suppressor Function , 2010, PloS one.

[27]  A. Alvero,et al.  Recent insights into the role of NF-kappaB in ovarian carcinogenesis , 2010, Genome Medicine.

[28]  T. Chou.  Drug combination studies and their synergy quantification using the Chou-Talalay method. , 2010, Cancer research.

[29]  D. Leake,et al.  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. , 2009, Cancer research.

[30]  M. Birrer,et al.  The Karyopherin proteins, Crm1 and Karyopherin β1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation , 2009, International journal of cancer.

[31]  S. Mutka,et al.  Identification of nuclear export inhibitors with potent anticancer activity in vivo. , 2009, Cancer research.

[32]  C. O'Neill,et al.  cis-Diamminedichloroplatinum(II)-induced cell death through apoptosis in sensitive and resistant human ovarian carcinoma cell lines , 2009, Cancer Chemotherapy and Pharmacology.

[33]  M. Karin,et al.  Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. , 2009 .

[34]  Michael Karin,et al.  Is NF-κB a good target for cancer therapy? Hopes and pitfalls , 2009, Nature Reviews Drug Discovery.

[35]  Carsten Denkert,et al.  Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer , 2008, Cancer.

[36]  V. Rotter,et al.  Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor alpha in cancer cells. , 2007, Cancer research.

[37]  M. Karin.  Nuclear factor-κB in cancer development and progression , 2006, Nature.

[38]  M. Karin.  Nuclear factor-kappaB in cancer development and progression. , 2006, Nature.

[39]  Pamela A. Silver,et al.  Nuclear transport and cancer: from mechanism to intervention , 2004, Nature Reviews Cancer.

[40]  Jose M. Silva,et al.  Intratumoral Heterogeneity in Microsatellite Alterations in BRCA1 and PTEN Regions in Sporadic Colorectal Cancer , 2003, Annals of Surgical Oncology.

[41]  R. Agarwal,et al.  Ovarian cancer: strategies for overcoming resistance to chemotherapy , 2003, Nature Reviews Cancer.

[42]  J. Qin,et al.  Parc A Cytoplasmic Anchor for p53 , 2003, Cell.

[43]  Bernd R. Binder,et al.  Signaling Molecules of the NF-κB Pathway Shuttle Constitutively between Cytoplasm and Nucleus* , 2002, The Journal of Biological Chemistry.

[44]  B. Binder,et al.  Signaling molecules of the NF-kappa B pathway shuttle constitutively between cytoplasm and nucleus. , 2002, The Journal of biological chemistry.

[45]  M. Cobb,et al.  Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. , 2001, Endocrine reviews.

[46]  T. Hope,et al.  An N‐terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IκBα , 1999 .

[47]  N. Kudo,et al.  Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[48]  G. Wahl,et al.  A leucine‐rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking , 1999, The EMBO journal.

[49]  T. Hope,et al.  An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IkappaBalpha. , 1999, The EMBO journal.

[50]  E. Newlands,et al.  Phase I trial of elactocin. , 1996, British Journal of Cancer.

[51]  A. Eastman,et al.  Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. , 1991, The Journal of clinical investigation.

[52]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[53]  J. Whang‐Peng,et al.  Characterization of a human ovarian carcinoma cell line (NIH:OVCAR-3) with androgen and estrogen receptors. , 1983, Cancer research.

[54]  R. Elashoff,et al.  Primary Cytoreductive Surgery for Epithelial Ovarian Cancer , 1983, Obstetrics and gynecology.

[55]  F. Harrell,et al.  Evaluating the yield of medical tests. , 1982, JAMA.