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XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

ABSTRACT: XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

PROVIDER: PRJNA688482 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13324109.fastq.gz	Fastqsanger.gz
	SRR13324110.fastq.gz	Fastqsanger.gz
	SRR13324111.fastq.gz	Fastqsanger.gz
	SRR13324112.fastq.gz	Fastqsanger.gz
	SRR13324113.fastq.gz	Fastqsanger.gz

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XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

Project description:The five-year survival rate remains less than 50% for high-risk neuroblastoma patients, few of them show effective response to current chemotherapy drugs. It is urgent to identify new therapeutic targets and corresponding drugs for high-risk neuroblastoma. Exportin-1(XPO1), also known as chromosomal region maintenance 1 (CRM1), plays important roles in the progress of tumorigenesis. However, the prognostic and therapeutic values of XPO1 in neuroblastoma have not been reported. Here, our results showed that overexpression of XPO1 was significantly associated with poor clinical characteristics and prognosis of neuroblastoma patients. The specific inhibitor of XPO1 suppressed neuroblastoma cell growth both in vitro and in vivo. Specifically, inhibition of XPO1 suppressed neuroblastoma cells proliferation and induced cell apoptosis by FOXO1 and RB1 nuclear accumulation in neuroblastoma through inhibiting PI3K/AKT pathway, and induced G0/G1 phase cell arrest by activating P53 function. Together, XPO1 is a promising prognostic indicator for neuroblastoma and a novel target for antitumor treatment by selective inhibitor verdinexor (KPT-335).

2021-08-18 | GSE163987 | GEO

XPO1 blockade with KPT-330 promotes apoptosis in Cutaneous T- cell Lymphoma by activating the p53-p21 and p27 pathways

Project description:To assess the effects of XPO1 inhibition with small molecule inhibitor KPT-330 on Cutaneous T-cell Lymphoma after 48 hours of treatment

2024-04-23 | GSE262491 | GEO

CRM1 inhibitor anti-tumor activity is enhanced with salicylates by S-phase arrest and impaired DNA-damage repair

Project description:Chromosome region maintenance protein1 (CRM1) mediates protein export from the nucleus and is a new target for anti-cancer therapeutics. Broader application of KPT-330 (Selinexor), a CRM1 inhibitor approved for myeloma, has been limited by toxicity. We found that combining choline salicylate (CS) with low-doses of KPT-330 (K+CS) had potent synergistic activity across blood and solid organ cancers ex-vivo and in-vivo. Mechanistically, K+CS enhances CRM1 degradation, induces potent inhibition of CRM1 mediated nuclear export, and arrests cells in S-phase with simultaneous reduction of Rad51 causing impaired DNA damage repair. K+CS represents a potential new class of therapy for multiple cancer types.

2020-10-28 | GSE160186 | GEO

Analysis of gene expression changes in KPT-185-treated HMLE cells transduced to stably overexpress SNAI1

Project description:HMLE-SNAIL cell cultures were treated with KPT-185 drug (KPT, 150 nanomolar) or vehicle (DMSO) for 24 hours, in parallel quadruplicates. KPT-185 is an Exportin 1 (XPO1) inhibitor with possible pluripotent or unexpected effects on cell signaling. Total RNA was isolated and analyzed in an Agilent two-color experiment, where four biological replicates of each condition were directly compared, expression ratios are KPT-treated condition relative to control (DMSO vehicle-treated).

2015-08-31 | GSE69326 | GEO

The XPO1 inhibitor KPT-8602 synergizes with dexamethasone for the inhibition of acute lymphoblastic leukemia

Project description:Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Survival of ALL patients has improved significantly over the last 50 years. However, the current intensified chemotherapy is associated with serious short and long-term side effects in these young patients. Whereas KPT-8602 is a second generation exportin-1 (XPO-1) inhibitor with potent activity against ALL in pre-clinical models and with minimal effects on normal cells. In this study, we evaluated if synergistic ALL inhibition could be obtained by combining KPT-8602 with dexamethasone, vincristine or doxorubicin. Combination of KPT-8602 with dexamethasone showed the strongest synergistic effect on human B-ALL and T-ALL cell lines. This synergy was confirmed in vivo on three patient-derived ALL xenografts. Compared to single drug treatment, the drug combination caused increased apoptosis, reduced cell cycle gene expression and led to histone depletion. mRNA expression analysis and ChIP-seq revealed that addition of KPT-8602 to dexamethasone increased transcript level and binding of the glucocorticoid receptor, as well as NFKBIA expression. Dexamethasone concentrations could be reduced 5 to 10-fold in the presence of KPT-8602 to achieve the same level of NFKBIA induction as with dexamethasone alone. Our pre-clinical study demonstrates that combination of KPT-8602 and dexamethasone is highly synergistic in vivo. This opens the possibility to reduce dexamethasone concentrations and reduce side effects in future clinical trials.

2019-08-05 | GSE135350 | GEO

High-throughput mRNA sequencing of CLL cells containing an E571K XPO1 mutations

Project description:Purpose: Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood. Thus, we aimed to identify disrupted cellular pathways in response to the E571K XPO1 mutation, the mutation most frequently cited in CLL patients, via high-throughput RNA-sequencing Results & Conclusion: Multidimensional scaling (MDS) analysis of the top 1000 most variable genes demonstrated distinctly unique clustering along the first dimension for XPO1-E571K patient and XPO1-wt patient samples. This clustering pattern was driven by a number of genes that were either over- or under-expressed in XPO1-E571K patient cells, contributing to a unique gene expression pattern in patients with this mutation signature.

2021-01-21 | GSE163370 | GEO

XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor verdinexor.

Project description:BackgroundHigh-risk neuroblastoma patients have a 5-year survival rate of less than 50%. It's an urgent need to identify new therapeutic targets and the appropriate drugs. Exportin-1 (XPO1), also known as chromosomal region maintenance 1, plays important roles in the progression of tumorigenesis. However, the prognostic and therapeutic values of XPO1 in neuroblastoma have not been reported.MethodsCorrelations between XPO1 expression level and clinical characteristics were analyzed using the Neuroblastoma Research Consortium (NRC) dataset and tissue microarray analysis. Cell proliferation assays, colony formation assays, apoptosis assays, cell cycle analysis were performed to analyze the anti-tumor effects of verdinexor (KPT-335) in vitro. Western blot and mRNA sequencing were performed to explore underlying mechanism. In vivo anti-tumor effects of verdinexor were studied in a neuroblastoma xenograft model.ResultsHigher XPO1 levels were associated with advanced stage and poor prognosis in neuroblastoma patients. The specific inhibitor of XPO1 verdinexor suppressed the neuroblastoma cell growth both in vitro and in vivo. Specifically, inhibition of XPO1 suppressed the neuroblastoma cell proliferation and induced cell apoptosis by nuclear accumulation of FOXO1 and RB1 in the neuroblastoma due to the inhibition of the PI3K/AKT pathway, and induced G0/G1 phase cell cycle arrest by activation of P53 function.ConclusionsXPO1 is a promising prognostic indicator for neuroblastoma and a novel target for antitumor treatment with selective inhibitor verdinexor.

| S-EPMC8359549 | biostudies-literature

The XPO1 inhibitor KPT-8602 synergizes with dexamethasone for the inhibition of acute lymphoblastic leukemia

Project description:The XPO1 inhibitor KPT-8602 synergizes with dexamethasone for the inhibition of acute lymphoblastic leukemia

| PRJNA558544 | ENA

Analysis of gene expression changes in KPT330-treated HMLE cells transduced to stably overexpress SNAI1

Project description:HMLE-SNAIL cell cultures were treated with KPT330 drug (KPT, 150 nanomolar) or vehicle (DMSO) for 24 hours, in parallel quadruplicates. KPT-330 is an Exportin 1 (XPO1) inhibitor with possible pluripotent or unexpected effects on cell signaling. Total RNA was isolated and analyzed in an Agilent two-color experiment, where four biological replicates of each condition were directly compared, expression ratios are KPT-treated condition relative to control (DMSO vehicle-treated) The experiment object was to identify genes that displayed significantly altered expression in response to KPT treatment inorder to confirm on-target drug impact and elucidate other potential effects in this cell line model.

2015-08-31 | E-GEOD-69326 | biostudies-arrayexpress

Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias.

Project description:As tyrosine kinase inhibitors (TKIs) fail to induce long-term response in blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL), novel therapies targeting leukemia-dysregulated pathways are necessary. Exportin-1 (XPO1), also known as chromosome maintenance protein 1, regulates cell growth and differentiation by controlling the nucleocytoplasmic trafficking of proteins and RNAs, some of which are aberrantly modulated in BCR-ABL1(+) leukemias. Using CD34(+) progenitors from CML, B-ALL, and healthy individuals, we found that XPO1 expression was markedly increased, mostly in a TKI-sensitive manner, in CML-BC and Ph(+) B-ALL. Notably, XPO1 was also elevated in Ph(-) B-ALL. Moreover, the clinically relevant XPO1 inhibitor KPT-330 strongly triggered apoptosis and impaired the clonogenic potential of leukemic, but not normal, CD34(+) progenitors, and increased survival of BCR-ABL1(+) mice, 50% of which remained alive and, mostly, became BCR-ABL1 negative. Moreover, KPT-330 compassionate use in a patient with TKI-resistant CML undergoing disease progression significantly reduced white blood cell count, blast cells, splenomegaly, lactate dehydrogenase levels, and bone pain. Mechanistically, KPT-330 altered the subcellular localization of leukemia-regulated factors including RNA-binding heterogeneous nuclear ribonucleoprotein A1 and the oncogene SET, thereby inducing reactivation of protein phosphatase 2A tumor suppressor and inhibition of BCR-ABL1 in CML-BC cells. Because XPO1 is important for leukemic cell survival, KPT-330 may represent an alternative therapy for TKI-refractory Ph(+) leukemias.

| S-EPMC3811176 | biostudies-literature

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