Targeting eIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer
Year: 2023
Type: article
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.
DOI: 10.1172/jci172503
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
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: Cancer Prevention and Research Institute of Texas, Memorial Sloan-Kettering Cancer Center, Syndax Pharmaceuticals, National Institutes of Health, University of Texas MD Anderson Cancer Center, Houston Methodist Research Institute, National Cancer Institute, National Center for Research Resources, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: EIF4A is a new therapeutic vulnerability in triple-negative breast cancer, G1569999668, G202784131, BD Biosciences Special Order LSRII, G2458094374, G2630554310, G2850151910, G2859315832, G3102002109, G345484959, Proteomics and Metabolomics Core Facility, Proteomics and Metabolomics Core Facility, Hormonal Regulation of Breast Cancer, Advanced Multiparameter Cytometry and Cell Sorting Core, G7837447426, G8153776008, G8271546232, G863484009, G9000007037, G9000008871, G9000010214, G9000027940, G9000132721, G9000194218, G9000240210, Baylor College of Medicine Cancer Center - Cancer Center Support Grant
OpenAlex ID: W4387909059