Redirecting traffic using the XPO1 police

Abraham, Sheela A.; Holyoake, Tessa L.

doi:10.1182/blood-2013-09-523670

Cited by 14 publications

(10 citation statements)

References 8 publications

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“…Inactivation of XPO-1 leads to intranuclear retention of tumor suppressor proteins thereby suppressing neoplastic cell division and tumor growth. Inactivation of the exportin also decreases the export of mRNAs of several protooncogenes to prevent their translation to proteins in the cytoplasm (5,6). Selinexor is currently under phase II/IIb clinical investigations for the evaluation of its activity against diffuse large B-cell lymphoma (DLBCL) and a variety of solid tumors (7).…”

Section: Introductionmentioning

confidence: 99%

XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB

Ming

Xie

et al. 2018

Molecular Cancer Therapeutics

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Inhibition of B-cell receptor (BCR) signaling through the BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one third of patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib. We found that selinexor had a broader antitumor activity in MCL than ibrutinib. MCL cell lines resistant to ibrutinib remained sensitive to selinexor. We showed that selinexor induced apoptosis/cell-cycle arrest and XPO-1 knockdown also retarded cell growth. Furthermore, downregulation of the NFkB gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NFkB was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IkB that was accompanied by the reduction of DNA-binding activity of NFkB, suggesting that NFkB is trapped in an inhibitory complex. Coimmunoprecipitation confirmed that p65 of NFkB and IkB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IkB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NFkB pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NFkB inhibition.

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Section: Introductionmentioning

confidence: 99%

XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB

Ming

Xie

et al. 2018

Molecular Cancer Therapeutics

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“…XPO1 inhibition locks cargo proteins, including TSPs, in the nucleus leading to selective apoptosis of cancer cells, whereas, normal cells undergo transient cell cycle arrest [14–29]. Selinexor (KPT-330) is a first–in-class orally bioavailable SINE compound that is currently being evaluated in multiple late stage clinical trials in patients with relapsed and/or refractory hematological and solid tumor malignancies [30–32].…”

Section: Introductionmentioning

confidence: 99%

Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death

et al. 2016

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The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells. Here, we demonstrated that NF-κB transcriptional activity is up-regulated in cells that are naturally resistant or have acquired resistance to SINE compounds. Resistance to SINE compounds was created by knockdown of the cellular NF-κB inhibitor, IκB-α. Combination treatment of selinexor with proteasome inhibitors decreased NF-κB activity, sensitized SINE compound resistant cells and showed synergistic cytotoxicity in vitro and in vivo. Furthermore, we showed that selinexor inhibited NF-κB activity by blocking phosphorylation of the IκB-α and the NF-κB p65 subunits, protecting IκB-α from proteasome degradation and trapping IκB-α in the nucleus to suppress NF-κB activity. Therefore, combination treatment of selinexor with a proteasome inhibitor may be beneficial to patients with resistance to either single-agent.

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“…Shuttling of specific proteins out of the nucleus is essential for the regulation of cell cycle and proliferation of both normal and malignant tissues [ 8 ]-[ 11 ]. Examples of nuclear effectors which are exported into the cytoplasm in cancer include the drug targets topoisomerase IIα [ 12 ] and BCR-ABL [ 13 ] and tumor suppressor proteins such as Rb [ 14 ], APC [ 15 ], p53 [ 16 ], p21 [ 17 ], and p27 [ 18 ] (reviewed in Table 1 ). This makes nuclear export inhibition a potential target for therapeutic intervention in cancer [ 19 ],[ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Nucleo-cytoplasmic transport as a therapeutic target of cancer

et al. 2014

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Shuttling of specific proteins out of the nucleus is essential for the regulation of the cell cycle and proliferation of both normal and malignant tissues. Dysregulation of this fundamental process may affect many other important cellular processes such as tumor growth, inflammatory response, cell cycle, and apoptosis. It is known that XPO1 (Exportin-1/Chromosome Region Maintenance 1/CRM1) is the main mediator of nuclear export in many cell types. Nuclear proteins exported to the cytoplasm by XPO1 include the drug targets topoisomerase IIα (topo IIα) and BCR-ABL and tumor suppressor proteins such as Rb, APC, p53, p21, and p27. XPO1 can mediate cell proliferation through several pathways: (i) the sub-cellular localization of NES-containing oncogenes and tumor suppressor proteins, (ii) the control of the mitotic apparatus and chromosome segregation, and (iii) the maintenance of nuclear and chromosomal structures. The XPO1 protein is elevated in ovarian carcinoma, glioma, osteosarcoma, pancreatic and cervical cancer. There is a growing body of research indicating that XPO1 may have an important role as a prognostic marker in solid tumors. Because of this, nuclear export inhibition through XPO1 is a potential target for therapeutic intervention in many cancers. The best understood XPO1 inhibitors are the small molecule nuclear export inhibitors (NEIs; Leptomycin B and derivatives, ratjadones, PKF050-638, valtrate, ACA, CBS9106, selinexor/KPT-330, and verdinexor/KPT-335). Selinexor and verdinexor are orally bioavailable, highly potent, small molecules that are classified as Selective Inhibitors of Nuclear Export (SINE). KPT-330 is the only NEI currently in Phase I/II human clinical trials in hematological and solid cancers. Of all the potential targets in nuclear cytoplasmic transport, the nuclear export receptor XPO1 remains the best understood and most advanced therapeutic target for the treatment of cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0085-1) contains supplementary material, which is available to authorized users.

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Redirecting traffic using the XPO1 police

Cited by 14 publications

References 8 publications

XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB

XPO1 Inhibitor Selinexor Overcomes Intrinsic Ibrutinib Resistance in Mantle Cell Lymphoma via Nuclear Retention of IκB

Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death

Nucleo-cytoplasmic transport as a therapeutic target of cancer

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