The XPO1 inhibitor KPT-8602 synergizes with dexamethasone for the inhibition of acute lymphoblastic leukemia
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ABSTRACT:
PROVIDER: PRJNA558544 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9899810.fastq.gz | Fastqsanger.gz | |||
| SRR9899820.fastq.gz | Fastqsanger.gz | |||
| SRR9899830.fastq.gz | Fastqsanger.gz | |||
| SRR9899801.fastq.gz | Fastqsanger.gz | |||
| SRR9899811.fastq.gz | Fastqsanger.gz |
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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
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
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
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
Project description:The TP53 wild-type cell line JVM2, representing mantle cell lymphoma (MCL), was transduced to create control or TP53 knockdown (KD) forms. These were then either left untreated or treated with KPT-185, a selective inhibitor of nuclear export (SINE) by XPO1, for gene expression profiling (GEP). Consistent with the observation that KPT-185 was equally toxic to both forms, the majority of gene expression changes resulting from KPT-185 treatment were similar for both forms, even though TP53 is known to be one of the cargo proteins of XPO1. GEP showed downregulation of genes involved in proliferation, consistent with findings of cell cycle analysis and supported by Western blot results. Quantitative proteomics revealed repression of ribosomal biogenesis to be a major TP53-independent effect of KPT-185.
2015-08-18 | GSE70479 | GEO
Project description:Mislocalization of oncogenes and tumor suppressors resulting from aberrant nuclear export promotes uncontrolled cell proliferation and growth transformation of cancer cells. We performed a genome-wide CRISPR-Cas9 screening in matched primary and KSHV-transformed cells, and identified genes that were pro-growth and growth-suppressive of both types of cells, of which exportin XPO1 was a critical factor for the survival of transformed cells. Using XPO1 inhibitor KPT-8602 and by siRNA-mediated knockdown, we confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells, as well as cell lines of other types of cancer including gastric cancer and liver cancer. XPO1 inhibition induced cell cycle arrest and p53 activation, which depended on the formation of PML nuclear bodies. Furthermore, XPO1 induced relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. Our findings highlight a novel mechanism of p53 activation and identify XPO1 as a vulnerable target of cancer cells.
2019-05-21 | GSE125507 | GEO
Project description:XPO1 gene encodes exportin 1 (XPO1) that controls the nuclear export of cargo proteins and RNAs. Almost 25% of primary mediastinal B-cell lymphomas (PMBL) and classical Hodgkin lymphomas (cHL) cases harboured a recurrent XPO1 point mutation (NM_003400, chr2:g61718472C>T) resulting in the E571K modification within the hydrophobic groove of the protein, the site of cargo proteins binding. We investigated the functional impact of XPO1E571K mutation using cell lines having various XPO1 status. We first confirmed that the mutation was present both within the XPO1 mRNA and the corresponding protein. In the U2940 cell line having a wild-type (wt) XPO1 gene, we introduced the E571K mutation using several CRISPR-Cas9 strategies. Using a barcoding method to trace the mutation, we observed that the mutation gave no advantage in vitro. Indeed, the effects of XPO1E571K mutation were hidden by the presence of the XPO1 wt allele. Strikingly, XPO1E571K mutation never occurred as homozygous or hemizygous in our patients��������� cohort. We further showed that XPO1E571K mutation modified selinexor binding to XPO1 and in turn, its sensitivity to this drug. We concluded that the balance between the wild-type and the mutated allele of XPO1 is a key element in defining XPO1 functions and oncogenic properties.
2020-10-01 | PXD016916 | Pride
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
Project description:Glucocorticoids are critical components of combination chemotherapy regimens in pediatric acute lymphoblastic leukemia (ALL). The pro-apoptotic BIM protein is an important mediator of glucocorticoid-induced apoptosis in normal and malignant lymphocytes, while the anti-apoptotic BCL2 confers resistance. The signaling pathways regulating BIM and BCL2 expression in glucocorticoid-treated lymphoid cells remain unclear. In this study, pediatric ALL patient-derived xenografts (PDXs) inherently sensitive or resistant to glucocorticoids were exposed to dexamethasone in vivo. In order to understand the basis for differential in vivo glucocorticoid sensitivity of PDXs, microarray analysis of gene expression was carried out on 5 each of dexamethasone-sensitive and resistant PDXs . This provided a global understanding of dexamethasone-induced signaling cascades in ALL cells in vivo, and especialy identified the genes that are involved in transducing the apoptotic signal, upstream of BIM/BCL2 dynamic interactions.
2014-05-20 | GSE57795 | GEO
Project description:An estimated 284,000 Americans will be diagnosed with breast cancer in 2021. Of these individuals, 15-20% will be diagnosed with basal-like triple-negative breast cancer (TNBC), which is known to be highly metastatic. Chemotherapy is standard of care for TNBC patients, but acquired chemoresistance is a common clinical problem. There is currently a lack of alternative, targeted treatment strategies for TNBC; this study sought to identify novel therapeutic combinations to treat basal-like TNBCs. For these studies, a set of four human basal-like TNBC cell lines was utilized to determine the cytotoxicity profile of 1,363 unique clinically-used drugs. Ten promising therapeutic candidates were identified, and synergism studies were performed in vitro. Two drug combinations that included KPT-330, an XPO1 inhibitor, were synergistic in all four cell lines. In vivo testing of four basal-like patient-derived xenografts identified a combination, KPT-330 and GSK2126458 (a PI3K/mTOR inhibitor), that decreased tumor burden in mice significantly more than monotherapy with either single agent. Bulk and single-cell RNA-sequencing, immunohistochemical studies, and analysis of published genomic datasets found that XPO1 was abundantly expressed in human basal-like TNBC cell lines, patient-derived xenografts, and patient tumor samples; within basal-like patients, XPO1 overexpression was associated with greater rates of metastases. These studies identify a promising new combination therapy for patients with basal-like TNBC.
2021-10-20 | GSE174391 | GEO