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 4

Zotatifin inhibits the translation of Sox4 and Fgfr1 mRNAs.

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Zotatifin inhibits the translation of Sox4 and Fgfr1 mRNAs. (A) Immunobl...
(A) Immunoblotting analysis of tumors that were treated with vehicle or zotatifin in vivo. n = 5 biological replicates per group. (B and C) qPCR analysis for Sox4 (B) and Fgfr1 (C) mRNA expression in tumors that were treated with vehicle or zotatifin in vivo. Data are presented as mean ± SEM and were analyzed using 2-tailed, unpaired Student’s t test. n = 5 biological replicates per group. (D) Immunoblotting analysis of 2153L cells that were treated with different concentrations of zotatifin for 6 hours in vitro. (E) Immunoblotting analysis of 2153L cells that were treated with 40 nM zotatifin for different time periods. (F) Immunoblotting analysis of BT549 cells that were treated with 40 nM zotatifin for different time periods. *Denotes a nonspecific band. In D–F, data are representative of 3 independent experiments. (G) Immunoblotting analysis of HAP1 cells that were treated with 40 nM zotatifin in vitro. Data are representative of 2 independent experiments. (H) Illustration for polysome profiling analysis. (I and J) Polysome profiling of 2153L cells that were treated with vehicle or 40 nM zotatifin for 2 hours. (I) Representative polysome profiles from 3 biological replicates. (J) Distribution of Sox4 and Fgfr1 mRNAs across the different fractions. Data are presented as mean ± SEM of 3 biological replicates. See complete unedited blots in the supplemental material.