Targeting eIF4A Triggers an Interferon Response to Synergize With Chemotherapy and Suppress Triple-Negative Breast Cancer

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

Publication Date

12-15-2023

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI172503

PMID

37874652

PMCID

PMC10721161

PubMedCentral® Posted Date

12-15-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, Humans, Interferons, Triple Negative Breast Neoplasms, Cell Line, Tumor, Antineoplastic Agents, Cell Proliferation, Tumor Microenvironment, Breast cancer, Immunotherapy, Translation, Oncology

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.

Comments

Associated Data