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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 Article has an altmetric score of 94

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

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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 7

Zotatifin synergizes with carboplatin to induce an IFN response and promote T cell–dependent tumor inhibition.

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Zotatifin synergizes with carboplatin to induce an IFN response and prom...
(A) Scheme of sample collection strategy for mass spectrometry. Tumor-bearing mice were randomized and treated with indicated therapies for 3 days. Tumor tissues were collected 3 hours after the second injection of zotatifin. n = 4 per group. (B and C) GSEA enrichment plot for Hallmark IFN-α response signature that is upregulated in combination therapy treated tumors compared with zotatifin monotherapy (B) or carboplatin monotherapy (C). (D) Heatmap for Hallmark IFN-α response signature proteins from tumor tissues treated with indicated therapies. (E–G) Mass cytometry analysis of tumor-infiltrating immune cells of 2153L tumors that were treated with indicated therapies for 7 days. (E) The uniform manifold approximation and projection (UMAP) plot overlaid with color-coded clusters. Data from 5 biological replicates of each group were concatenated before UMAP and FlowSOM clustering analysis. Equal numbers of events are shown for each group and major cell types are marked. (F) UMAP plot overlaid with the expression of Bst2 or granzyme B. (G) Quantification of major lymphoid populations from 2153L tumors in mass cytometry analysis. n = 5 biological replicates per group. (H) Outline of treatment design. Freshly dissociated 2153L tumor cells were transplanted into nude mice or BALB/c mice in parallel. Treatment was initiated when tumors reached 100 mm3. (I) Growth curves of 2153L tumors in nude mice treated with indicated drugs. n = 5 biological replicates per group. (J) Growth curves of 2153L tumors in BALB/c mice treated with indicated drugs. n = 3 biological replicates for monotherapy groups and n = 10 biological replicates for the combination treatment group. In I and J, data are presented as mean ± SEM and were analyzed using 2-way ANOVA with Bonferroni’s multiple-comparison test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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