The EIF4A inhibitor Zotatifin reprograms the translatome and the tumor immune microenvironment to suppress triple-negative breast cancer
Introduction
Protein synthesis is frequently dysregulated in cancers and selective inhibition of translation represents an attractive and understudied target for cancer therapy. The eukaryotic translation initiation factor 4A (eIF4A) is an RNA helicase that unwinds secondary structures in the 5′-UTR of mRNAs to facilitate translation initiation. Multiple tumor-promoting genes require enhanced eIF4A activity for translation. Zotatifin, the first-in-class eIF4A inhibitor, is currently undergoing a Phase I/II clinical trial for heavily pretreated ER+ breast cancers (NCT04092673), where partial responses were observed (5 of 19) when Zotatifin was combined with fulvestrant and abemaciclib. However, the effects of Zotatifin on triple-negative breast cancer (TNBC) and its interactions with chemotherapy or immunotherapy have not been reported in immuno-competent models. Our study aimed to investigate the effects and mechanisms of Zotatifin on tumor progression and metastasis, both as a monotherapy and in combination with chemo- or immuno-therapy, using diverse syngeneic TNBC mouse models.
Methods
We assessed Zotatifin efficacy using syngeneic models representing various molecular subtypes of TNBC. We employed proteomics profiling and mass cytometry to elucidate treatment response mechanisms and the impact on the tumor immune microenvironment.
Results
Therapeutically targeting eIF4A with Zotatifin exhibited pleiotropic effects on both tumor cells and the tumor immune microenvironment. In primary tumors, Zotatifin induced a repolarization of macrophages towards an M1-like phenotype and inhibited neutrophil infiltration. These effects sensitized tumors to immune checkpoint blockade. Mechanistic studies revealed that Zotatifin selectively inhibited the translation of Sox4 and Fgfr1, and induced an interferon response uniformly across models. The induction of an interferon response was partly attributed to the inhibition of Sox4 translation by Zotatifin. A similar induction of interferon-stimulated genes was observed in ER+ breast cancer patient biopsies following Zotatifin treatment. Surprisingly, Zotatifin synergized significantly with carboplatin to trigger DNA damage and an enhanced interferon response, resulting in T cell-dependent tumor suppression. Upon tail vein injection of tumor cells, Zotatifin monotherapy markedly reduced neutrophil infiltration and lung metastatic burden.
Conclusion
These studies revealed a vulnerability of eIF4A in TNBC, identified potential pharmacodynamic biomarkers for Zotatifin, and provided a rationale for new combination regimens comprising Zotatifin and chemotherapy or immunotherapy as treatments for TNBC.