Selinexor, a First-in-Class XPO1 Inhibitor, Is Efficacious and Tolerable in Patients with Myelodysplastic Syndromes Refractory to Hypomethylating Agents
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ABSTRACT:
PROVIDER: PRJNA592354 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10555303_1.fastq.gz | Fastqsanger.gz | |||
| SRR10555303_2.fastq.gz | Fastqsanger.gz | |||
| SRR10555304_1.fastq.gz | Fastqsanger.gz | |||
| SRR10555304_2.fastq.gz | Fastqsanger.gz | |||
| SRR10555305_1.fastq.gz | Fastqsanger.gz |
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Project description:PURPOSE The median overall survival (OS) of patients with high-risk myelodysplastic syndromes (MDS) refractory to hypomethylating agents is less than 6 months and there is no standard therapy for such patients. Preclinical studies have shown that inhibition of the nuclear export protein XPO1 causes nuclear accumulation of p53 and disruption of NF-κB signaling, both relevant targets for MDS. We therefore sought to determine the safety, efficacy, and potential molecular correlates of response to selinexor, an oral selective inhibitor of XPO1, in MDS. PATIENTS AND METHODS We report the results of a phase 2 clinical trial of selinexor in high-risk MDS patients refractory to hypomethylating agents. The primary endpoint was overall response rate (ORR) and secondary endpoints included safety, response duration, and OS. RESULTS In 19 evaluable patients, ORR was 32% (95% CI, 13-57) with an additional 42% (95% CI, 24-71) achieving stable disease (SD). Median OS was 9.6 months (95% CI, 8.5-17.1) with median follow-up of 2.1 years. Grade 3 or 4 adverse events (AEs) in the first 3 patients (thrombocytopenia [n=3] and hyponatremia [n=1]) led to dose reduction to 60mg flat dose twice-weekly for two weeks followed by one week off, resulting in significantly improved tolerability. The most frequent adverse event (AE) thereafter was grade 1 or 2 nausea, anorexia and fatigue. These and other AEs were manageable with supportive care implementation. The presence of an SF3B1 mutation was significantly associated with response to selinexor (p=0.02) and correlative studies suggest splicing alterations were induced by selinexor and affected inflammatory pathways such as NF-κB. CONCLUSIONS Selinexor is safe and tolerable in MDS when given at 60mg twice weekly for two weeks with one week off. Responses were enriched in SF3B1 mutated patients.
2020-11-26 | GSE141147 | GEO
Project description:Neuroblastoma accounts for 15% of cancer-related deaths in children, highlighting an unmet need for novel therapies. Selinexor is a small molecule inhibitor of XPO1 that shuffles cargo proteins with a nuclear export sequence, many of which are essential for cancer growth and cell maintenance, from the nucleus to the cytosol. We systematically tested the effect of selinexor against neuroblastoma cells in vitro and in vivo and used a proteomics screening approach to interrogate unknown mechanisms of action. We found that selinexor induces its cytotoxic effects in neuroblastoma through the nuclear accumulation of p53. By combining selinexor with an aurora kinase inhibitor, alisertib that is already in clinical use for neuroblastoma, we show that p53-mediated lethality can be further augmented supporting clinical testing of this drug combination against neuroblastoma
2023-03-11 | PXD026454 | Pride
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:In order to characterize the dynamics of proteins between different cellular compartments in response to selinexor (XPO1 inhibitor), MK-2206 (Akt inhibitor) an the combination i AML cells, we treated MV4-11 and PL-21 cells for 6 hours with DMSO, 1 uM selinexor, 1 uM MK-2206 or the combination. Each condition was performed in 4 biological bio-reps.
2022-08-07 | PXD033527 | Pride
Project description:Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited treatment options. This study investigates the potential of repurposing selinexor, an XPO1 inhibitor, as a novel therapeutic option for TNBC. By utilizing a computational drug repurposing approach, XPO1 inhibitors were identified to be preferentially sensitive in TNBC compared to other breast cancer subtypes and its efficacy validated in an independent patient dataset and across various TNBC cell lines. Using RNA-sequencing after longitudinal XPO1 inhibition in a panel of TNBC cell lines and western blotting, we reveal that XPO1 inhibitor induces TNBC cell death by inhibiting the NF-kB pathway through nuclear retention of NFKBIA, a key regulator of this pathway. These findings suggest that XPO1 inhibitors could be an effective targeted therapy for TNBC and paves the way for more personalized treatment strategies offering hope for better outcomes in TNBC patients.
2024-12-02 | GSE278241 | GEO
Project description:Inhibition of BCR signaling through BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one-third of the 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 anti-tumor 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. Further, down-regulation of the NF-B gene signature, as opposed to BCR signature, was a common feature that underlies the response of MCL to both selinexor and ibrutinib. Meanwhile, unaltered NF-B was associated with ibrutinib resistance. Mechnistically, selinexor induced nuclear retention of IB that was accompanied by the reduction of DNA binding activity of NF-B suggesting that NF-B is trapped in an inhibitory complex. Co-immunoprecipitation confirmed that p65 of NF-B and IB were physically associated. In primary MCL tumors, we further demonstrated that the number of cells with IB nuclear retention was linearly correlated with the degree of apoptosis. Our data highlight the role of NF-B pathway in drug response to ibrutinib and selinexor and show the potential of using selinexor to prevent and overcome intrinsic ibrutinib resistance through NF-B inhibition.
2018-07-10 | GSE116810 | GEO
Project description:Selinexor is an orally bioavailable, small-molecule selective inhibitor of nuclear export protein that has been approved for the clinical treatment of relapsed or refractory multiple myeloma. At present, some studies have found that Selinexor can play an anti-inflammatory role in sepsis. We found that Selinexor, a selective inhibitor of XPO1, can alleviate bleomycin-induced pulmonary fibrosis in mice in our research work, but the specific mechanism is still unclear. After Selinexor treatment of bleomycin-induced pulmonary fibrosis in mice, we detected some differentially expressed proteins through proteomics, which may be the key mechanism of alleviating pulmonary fibrosis.
2023-08-01 | PXD044259 |
Project description:The transcription factor GATA-3 and the transcriptional program it regulates have emerged as oncogenic drivers across diverse T-cell lymphomas (TCL), many of which are resistant to conventional chemotherapeutic agents and characterized by recurrent losses of key tumor suppressor genes, including TP53 and PTEN, both of which are clients of the nuclear export protein XPO1. Here we demonstrated that XPO1 is highly expressed by malignant T cells expressing GATA-3 and by lymphoma-associated macrophages (LAM) within their tumor microenvironment (TME). Using complementary genetically engineered mouse (GEM) models, we demonstrated that TP53 and/or PTEN deficient TCL, and LAM within their TME, are sensitive to the selective XPO1 antagonist selinexor. In an effort to identify TP53 and PTEN independent mechanisms, we used complementary and orthogonal approaches to investigate the role of eIF4e and XPO1-dependent mRNA nuclear export in these TCL. We identified a novel role for eIF4E/XPO1 in exporting GATA-3 and GATA-3-dependent transcripts from the nucleus in TCL, and in the export of therapeutically relevant transcripts, including CSF-1R, from LAM. Therefore, XPO1 antagonism, by impairing oncogenic transcriptional programs in TCL and depleting LAM from their TME, is a novel approach to target two independent dependencies in a group of therapeutically challenging TCL.
2024-12-31 | GSE267408 | GEO
Project description:Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1-MLF1 and NPM1-CCDC28A. NPM1-MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay (2/12). NPM1-CCDC28A localizes predominantly to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently (5/6) induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. Thus, our study provides experimental evidence that both NPM1-MLF1 and NPM1-CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 may be a promising strategy for the NPM1-rearranged AML.
2024-08-14 | GSE274558 | GEO
Project description:Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1-MLF1 and NPM1-CCDC28A. NPM1-MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay (2/12). NPM1-CCDC28A localizes predominantly to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently (5/6) induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. Thus, our study provides experimental evidence that both NPM1-MLF1 and NPM1-CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 may be a promising strategy for the NPM1-rearranged AML.
2024-08-14 | GSE274559 | GEO