ArticleCell death & disease2019
XPO1 inhibitor KPT-330 synergizes with Bcl-xL inhibitor to induce cancer cell apoptosis by perturbing rRNA processing and Mcl-1 protein synthesis.
Article in Cell death & disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 45 citations in OpenAlex.
- XPO1: From basic research to clinical treatment (Review).Oncology reports · 2026Review
- OT-55 reshapes tolerogenic BH3-mimetic-induced apoptosis toward immunogenic cell death in acute myeloid leukemia, potentiating PD-1/Tim-3 blockade.Cell death & disease · 2026Article
- Article
- Selinexor enhances temozolomide efficacy in glioblastoma through modulation of multiple resistance-associated mechanisms.Frontiers in oncology · 2026Article
- Review
- Selinexor, a selective inhibitor of nuclear export, shows anti-proliferative and anti-migratory effects on male germ cells in vitro.BMC pharmacology & toxicology · 2025Article
- Review
- Selinexor as a Therapeutic Target: Advances in Non-small Cell and Small Cell Lung Cancer Treatment Strategies.Recent patents on anti-cancer drug discovery · 2025Review
- Therapeutic targeting of exportin-1 beyond nuclear export.Trends in pharmacological sciences · 2025Review
- Discovery, Validation and Mechanistic Study of XPO1 Inhibition in the Treatment of Triple-Negative Breast Cancer.Cancers · 2024Article
- The RNA helicases DDX19A/B modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export in leukemia cells.Leukemia · 2024Article
- Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.Cellular & molecular immunology · 2024Article
- Pooled multicolour tagging for visualizing subcellular protein dynamics.Nature cell biology · 2024Article
- The nuclear export protein exportin-1 in solid malignant tumours: From biology to clinical trials.Clinical and translational medicine · 2024Review
- XPO1 blockade with KPT-330 promotes apoptosis in cutaneous T-cell lymphoma by activating the p53-p21 and p27 pathways.Scientific reports · 2024Article
- Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation.Nature communications · 2024Article
- Unraveling the complexity of drug resistance mechanisms to SINE, T cell-engaging therapies and CELMoDs in multiple myeloma: a comprehensive review.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Article
- The efficacy of selinexor (KPT-330), an XPO1 inhibitor, on non-hematologic cancers: a comprehensive review.Journal of cancer research and clinical oncology · 2023Review
- ADAR1 and ZBP1 in innate immunity, cell death, and disease.Trends in immunology · 2023Review
Corrections and comments
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Authors and funding
5 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
XPO1 (exportin1) mediates nuclear export of proteins and RNAs and is frequently overexpressed in cancers. In this study, we show that the orally bioavailable XPO1 inhibitor KPT-330 reduced Mcl-1 protein level, by which it synergized with Bcl-xL inhibitor A-1331852 to induce apoptosis in cancer cells. KPT-330/A-1331852 combination disrupted bindings of Mcl-1 and Bcl-xL to Bax, Bak, and/or Bim, elicited mitochondrial outer membrane permeabilization, and triggered apoptosis. KPT-330 generally mitigated mRNA expression and protein synthesis rather than mRNA nuclear export or protein stability of Mcl-1. KPT-330 inhibited mTORC1/4E-BP1 and Mnk1/eIF4E axes, which disrupted the eIF4F translation initiation complex but was dispensable for Mcl-1 reduction and KPT-330/A-1331852 combination-induced apoptosis. Mature rRNAs are integral components of the ribosome that determines protein synthesis ability. KPT-330 impeded nucleolar rRNA processing and reduced total levels of multiple mature rRNAs. Reconstitution of XPO1 by expressing degradation-resistant C528S mutant retained rRNA amount, Mcl-1 expression, and Bcl-xL inhibitor resistance upon KPT-330 treatment. KPT-330/A-1331852 combination suppressed growth and enhanced apoptosis of non-small cell lung cancer xenografts. Therefore, we clarify the reason of apoptosis resistance of cancer cells to XPO1 inhibition and develop a potential strategy for treating solid tumors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.