ArticleThe Journal of clinical investigation2023
Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- Unraveling Biomarker Signatures in Triple-Negative Breast Cancer: A Systematic Review for Targeted Approaches.International journal of molecular sciences · 2024Pooled it
- MERTK inhibition cooperates with immunomodulatory cyclophosphamide to induce CXCL9⁺ monocyte-macrophage programming and durable antitumor immunity in triple negative breast cancer.Cancer immunology research · 2026Article
- Targeting eIF4A-dependent translation in genetically complex sarcoma.JCI insight · 2026Article
- Proteomic characterization of intrahepatic cholangiocarcinoma identifies risk-stratifying subgroups and EIF4A1 as a therapeutic target.Nature communications · 2026Article
- Genotype-Encoded UV Sensitivity in iPSC-Derived Human Melanocytes Reveals MX2 as a Physiological Amplifier of p53/p38-Mediated DNA Damage Signaling.International journal of molecular sciences · 2026Article
- CELF1 is a non-canonical eIF4E binding protein that promotes translation of epithelial-mesenchymal transition effector mRNAs.Nucleic acids research · 2026Article
- MERTK inhibition cooperates with immunomodulatory cyclophosphamide to induce CXCL9bioRxiv : the preprint server for biology · 2026Article
- Broad-spectrum antiviral activity of the synthetic rocaglate zotatifin against Mayaro virus and other viruses.Frontiers in cellular and infection microbiology · 2026Article
- Peptide antibody tools to dissect specific functions of eIF4A paralogs in cancer.Discover oncology · 2025Article
- Spatial Transcriptomics Reveals Transcriptomic and Immune Microenvironment Reprogramming during Thyroid Carcinoma Dedifferentiation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Blocking NRF2 Translation by Inhibition of Cap-Dependent Initiation Sensitizes Lymphoma Cells to Ferroptosis and CAR T-cell Immunotherapy.Cancer research · 2025Article
- RNA-binding proteins DND1 and NANOS3 cooperatively suppress the entry of germ cell lineage.Nature communications · 2025Article
- eIF4F-mediated dysregulation of mRNA translation in cancer.RNA (New York, N.Y.) · 2025Review
- Short- and long-term efficacy of olaparib combined with chemotherapy in advanced triple-negative breast cancer.American journal of cancer research · 2025Article
- Eukaryotic initiation factors: central factor associating mRNA translational plasticity during neuropathic pain progression.Frontiers in neurology · 2025Review
- Immune Modulatory Profile of the Pateamines PatA and Des-Methyl Des-Amino PatA.International journal of molecular sciences · 2024Article
- Reprograming immunosuppressive microenvironment by eIF4G1 targeting to eradicate pancreatic ductal adenocarcinoma.Cell reports. Medicine · 2024Article
- Pharmacologic Inhibition of EIF4A Blocks NRF2 Synthesis to Prevent Osteosarcoma Metastasis.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer.JCI insight · 2024Article
- Genetic evidence supporting potential causal roles of EIF4 family in breast cancer: a two-sample randomized Mendelian study.Scientific reports · 2024Article
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Authors and funding
21 authors at 4 institutions in 2 countries.
Funding
Abstract
Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A with zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages toward an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox4 and Fgfr1, and induces an interferon (IFN) response uniformly across models. The induction of an IFN response is partially due to the inhibition of Sox4 translation by zotatifin. A similar induction of IFN-stimulated genes was observed in breast cancer patient biopsies following zotatifin treatment. Surprisingly, zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened IFN response, resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for zotatifin, and provide a rationale for new combination regimens consisting of zotatifin and chemotherapy or immunotherapy as treatments for TNBC.
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Registered trials
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.