Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer
Na Zhao, … , Charles M. Perou, Jeffrey M. Rosen
Na Zhao, … , Charles M. Perou, Jeffrey M. Rosen
Published October 24, 2023
Citation Information: J Clin Invest. 2023;133(24):e172503. https://doi.org/10.1172/JCI172503.
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Research Article Oncology

Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer

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.

Authors

Na Zhao, Elena B. Kabotyanski, Alexander B. Saltzman, Anna Malovannaya, Xueying Yuan, Lucas C. Reineke, Nadia Lieu, Yang Gao, Diego A. Pedroza, Sebastian J. Calderon, Alex J. Smith, Clark Hamor, Kazem Safari, Sara Savage, Bing Zhang, Jianling Zhou, Luisa M. Solis, Susan G. Hilsenbeck, Cheng Fan, Charles M. Perou, Jeffrey M. Rosen

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Figure 3

Zotatifin remodels the proteomic landscape of 2153L tumors.

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Zotatifin remodels the proteomic landscape of 2153L tumors. (A) Scheme o...
(A) Scheme of sample collection strategy for mass spectrometry. Freshly dissociated 2153L tumor cells were transplanted into the fourth mammary fat pad of BALB/c mice and were allowed to grow until palpable. Mice then were randomized and treated with either vehicle or zotatifin for 2 doses spanning 3 days. Tumor tissues were collected 3 hours after the second injection. (B) Volcano plot showing relative fold change (log2) in protein abundance versus −log10(P values) from 2153L tumors treated with zotatifin compared with vehicle. Proteins that demonstrate a significant change in expression (FDR q < 0.05) are colored, with decreased expression on the left in blue and increased expression on the right in red. Genes that are critically involved in cell proliferation, stem cell signaling, and IFN response pathways are labeled. n = 4 biological replicates per arm. Statistical significance was determined by 2-tailed, unpaired moderated t test. (C) GSEA of mass spectrometry results was performed with the MSigDB hallmarks data set and is summarized as the normalized enrichment score (NES) in vehicle- or zotatifin-treated 2153L tumor tissues. Top pathways that have a family-wise error rate (FWER) P < 0.25 are displayed. FWER P values for each pathway are denoted by color. (D) GSEA enrichment plots for Hallmark E2F targets and G2M checkpoint signatures that are downregulated in zotatifin-treated tumors compared with vehicle. (E) GSEA enrichment plots for Hallmark IFN-α response and IFN-γ response signatures that are upregulated in zotatifin-treated tumors compared with vehicle.