| Autor: |
Zhao N; Department of Molecular and Cellular Biology., Kabotyanski EB; Department of Molecular and Cellular Biology., Saltzman AB; Mass Spectrometry Proteomics Core., Malovannaya A; Mass Spectrometry Proteomics Core.; Department of Biochemistry and Molecular Pharmacology, and., Yuan X; Department of Molecular and Cellular Biology., Reineke LC; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA., Lieu N; Department of Molecular and Cellular Biology., Gao Y; Department of Molecular and Cellular Biology., Pedroza DA; Department of Molecular and Cellular Biology., Calderon SJ; Department of Molecular and Cellular Biology., Smith AJ; Department of Molecular and Cellular Biology., Hamor C; Department of Molecular and Cellular Biology., Safari K; Texas A&M Health Science Center, Houston, Texas, USA., Savage S; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA., Zhang B; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA., Zhou J; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Solis LM; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Hilsenbeck SG; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA., Fan C; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA., Perou CM; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA., Rosen JM; Department of Molecular and Cellular Biology. |
| Abstrakt: |
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. |
