Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells

Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

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“…Overcomes resistance to platinum compounds [166] In vitro Synergizes with DNA-damaging agents [187] Pediatric cancer (solid and hematological)…”

Section: In Vitromentioning

confidence: 99%

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

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“…In vitro studies have demonstrated cell cycle arrest, accumulation of DNA damage, and induction of apoptosis in response to treatment with SINE compounds as a result of the nuclear accumulation and reactivation of TSPs and reduced oncoproteins. 1,2,[13][14][15] We and others have previously shown that selinexor has anti-tumor activity in preclinical models of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), T-cell acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma (DLBCL). [2][3][4][15][16][17][18][19] In addition, selinexor is being tested as a single agent and in combination in ongoing phase 1 to 3 clinical trials for the treatment of advanced solid tumor and hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies

et al. 2020

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The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies. However, many tumors are not responsive to venetoclax. We used models of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) to determine in vitro and in vivo responses to treatment with venetoclax and SINE compounds combined. Cotreatment with venetoclax and SINE compounds demonstrated loss of viability in multiple cell lines. Further in vitro analyses showed that this enhanced cell death was the result of an increase in apoptosis that led to a loss of clonogenicity in methylcellulose assays, coinciding with activation of p53 and loss of MCL1. Treatment with SINE compounds and venetoclax combined led to a reduction in tumor growth in both AML and DLBCL xenografts. Immunohistochemical analysis of tissue sections revealed that the reduction in tumor cells was partly the result of an induction of apoptosis. The enhanced effects of this combination were validated in primary AML and DLBCL patient cells. Our studies reveal synergy with SINE compounds and venetoclax in aggressive hematologic malignancies and provide a rationale for pursuing this approach in a clinical trial.

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“…XPO1 mediates the nuclear exit of Cyclin Dependent Kinase (CDK)-cyclins such as cyclin B1 (which regulates transition from G2 to M phase), tumor suppressor proteins including p53, p21, Rb and FOXO that regulate CDK-cyclins and the progression of the cell cycle 28 , 29 . Previous studies with SINE compounds have shown reduced cell division in cancer cells 30 . RSV subverts the progression of cell cycle at both mRNA and protein levels.…”

Section: Resultsmentioning

confidence: 92%

Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication

Mathew

Tamir

Tripp

et al. 2021

Sci Rep

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Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, the elderly and immunocompromised individuals. Therapy for RSV infections is limited to high risk infants and there are no safe and efficacious vaccines. Matrix (M) protein is a major RSV structural protein with a key role in virus assembly. Interestingly, M is localised to the nucleus early in infection and its export into the cytoplasm by the nuclear exporter, exportin-1 (XPO1) is essential for RSV assembly. We have shown previously that chemical inhibition of XPO1 function results in reduced RSV replication. In this study, we have investigated the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds, KPT-335 and KPT-185. Our data shows that therapeutic administration of the SINE compounds results in reduced RSV titre in human respiratory epithelial cell culture. Within 24 h of treatment, RSV replication and XPO1 expression was reduced, M protein was partially retained in the nucleus, and cell cycle progression was delayed. Notably, the effect of SINE compounds was reversible within 24 h after their removal. Our data show that reversible inhibition of XPO1 can disrupt RSV replication by affecting downstream pathways regulated by the nuclear exporter.

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Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells

Cited by 9 publications

References 55 publications

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Venetoclax response is enhanced by selective inhibitor of nuclear export compounds in hematologic malignancies

Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication

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