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Dual inhibition of CDK4/6 and XPO1 induced senescence with acquired vulnerability to CRBN-based PROTAC drugs

ABSTRACT: We treated liver cancer cells with vehicle, CDK4/6 inhibitor, XPO1 inhibitor and the combination. Then, RNA sequencing was conducted to quantify the mRNA expression level of vehicle-treated or CDK4/6 inhibitor, XPO1 inhibitor and the combination treated liver cancer cells. CDK4/6 inhibitor, XPO1 inhibitor and the combination induced expression changes were obtained based on the processed data.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233531 | GEO | 2026/01/01

REPOSITORIES: GEO

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Dual inhibition of CDK4/6 and XPO1 induced senescence with acquired vulnerability to CRBN-based PROTAC drugs.

Project description:We first treated senescent liver cancer cells with vehicle or ARV-825 for 48 hours. Then, RNA sequencing was conducted to quantify the mRNA expression level of vehicle-treated or ARV-825-treated liver cancer cells. ARV-825-induced expression changes were obtained based on the resultant data.

2026-01-01 | GSE233770 | GEO

Dual inhibition of CDK4/6 and XPO1 induced senescence with acquired vulnerability to CRBN-based PROTAC drugs.

Project description:Dual inhibition of CDK4/6 and XPO1 induced senescence with acquired vulnerability to CRBN-based PROTAC drugs.

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Dual inhibition of CDK4/6 and XPO1 induced senescence with acquired vulnerability to CRBN-based PROTAC drugs

Project description:Dual inhibition of CDK4/6 and XPO1 induced senescence with acquired vulnerability to CRBN-based PROTAC drugs

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Targeting CDK4/6 impairs RB1/E2F activity to overcome the resistance to selinexor in Nature killer/T-cell lymphoma

Project description:XPO1 is frequently overexpressed in multiple hematological malignancies, highlighting the attractiveness of targeting XPO1 as a therapeutic strategy. However, the therapeutic potential of XPO1 inhibition in NKTL was still not well documented. Here, we demonstrated that XPO1 is highly expressed in NKTL and is correlated with poor prognosis, suggesting that XPO1 is a potential target in NKTL. In addition, we identified YY1 as a transcriptional factor that bound to XPO1 promoter to activate its expression. Functional studies revealed that pharmacological inhibition of XPO1 using selinexor effectively blocks CDK4/6-pRB-E2F-c-Myc signaling, resulting in cell cycle arrest and apoptosis in sensitive cells. Transcriptomic analysis identified that dysfunction in cell cycle machinery may contribute to selinexor resistance, as resistant cells restore the expression of cycle-related genes to evade cell death. High-throughput screening utilizing a panel of 130 cell cycle inhibitors identified CDK4/6 inhibitors as sensitizers to selinexor in resistant cells. Mechanistically, the combination of CDK4/6 inhibitors and selinexor led to an enhanced inhibition of pRB-E2F-c-Myc signaling. Additionally, compassionate use of selinexor in combination with chemotherapy (gemcitabine, oxaliplatin) in three Refectory/Relapsed (R/R) NKTL patients achieved favorable clinical outcomes. Our data unveil a novel mechanism by which XPO1 inhibition blocks CDK4/6-pRb-E2F-c-Myc signaling, providing a rationale for the combination of CDK4/6 with XPO1 inhibitors for NKTL treatment.

2025-05-13 | GSE230615 | GEO

CRISPR-Cas9 screening of KSHV-transformed cells identifies XPO1 as a vulnerable target of cancer cells by inducing p62 SQSTM1-mediated p53 activation in PML bodies

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

Discovery, Validation and Mechanistic study of XPO1 inhibition in the Treatment of Triple Negative Breast Cancer

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

XPO1 amplification abrogates the effects of E571K XPO1 mutation in B-cell lymphoma

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

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

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

Effects of the Combination Therapy of a CDK4/6 and a MEK inhibitor in a Mouse Model of Diffuse Midline Glioma

Project description:Diffuse intrinsic pontine glioma (DIPG) arises in the brainstem of children, leading tumor-related death among children. A heterozygous histone H3.3K27M mutation has been shown to occur in ~80% of DIPGs, and results in brainstem gliomagenesis. There is no clinical trial for the patients with DIPG that proved to prolong survival time so far. Recently, CDK4/6 inhibitor showed feasibility and early therapeutic effect against DIPG. Also, recent research with human DIPG specimens have detected the MAPK pathway highly activated. Here, we evaluated a novel combination therapy with CDK4/6 inhibitor and MEK inhibitor to the mouse DIPG model. In order to generate DIPG‐bearing mice, we are using the RCAS/Tv‐a system, with which we are able to target specific genetic alterations in RCAS viruses (avian retroviruses) to specific cells‐of‐origin using transgenic Tv‐a‐expressing mice (Tv‐a being the receptor for RCAS viruses). We injected P3‐P5 Nestin-Tv-a;p53fl/fl mice (C56Bl/6 background) with RCAS‐PDGF‐A + RCAS‐H3.3K27M, and RCAS-Cre. The mice are treated with vehicle (methylcellurose), ribociclib as monotherapy, trametinib as monotherapy, and ribociclib and combination as combination. For short-term use, tumor tissues treated with ribociclib showed cytostatic effect, and those treated with trametinib showed cytotoxic effect, and those with combination showed both. Long-term use showed that combination therapy modestly prolonged mice survival compared with vehicle. Therefore, we need to find how DIPG showed registence to the long-term chemotherapy.

2021-09-28 | GSE184786 | GEO

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