Abstract B007: Unexpected synthetic lethality mechanisms in eIF4A-targeted therapy

Abstract BACKGROUND Dysregulation of mRNA translation, which is prevalent in cancer, presents an underexplored therapeutic vulnerability. The eukaryotic translation initiation factor 4A (eIF4A) promotes protein synthesis by unwinding secondary structures in the 5’-untranslated region of mRNAs to facilitate translation initiation. While perturbation of eIF4A minimally affects the health normal cells, it is crucial for the translation of many oncogenes and is considered essential in most cancer cell lines. Zotatifin, a first-in-class eIF4A inhibitor, is currently under evaluation in a Phase I/II clinical trial for KRAS-mutant tumors and ER+ breast cancers. In addition to the tumor-intrinsic effect, our recent publication in the Journal of Clinical Investigation revealed that pharmacological targeting of eIF4A not only affects tumor cells but also improves the tumor immune microenvironment. This results in tumor inhibition, heightened sensitivity to immune checkpoint blockade, and remarkable synergism with platinum in various preclinical triple-negative breast cancer mouse models. OBJECTIVES To investigate the mechanism underlying the synergy between eIF4A-targeted therapy and platinum. UNPUBLISHED RESULT Mass spectrometry proteomic analysis coupled with ELISA and qPCR analysis unveiled that eIF4A-targeted therapy promotes type I interferon (IFN) secretion and induces a robust type I IFN response both in vivo and in vitro. This suggests a tumor cell-autonomous effect of IFN induction by eIF4A inhibition. Combining platinum with eIF4A-targeted therapy further heightens the type I IFN response in vivo, leading to T cell-and macrophage-dependent synergistic tumor regression. Interestingly, this synergy was not observed in vitro, indicating the involvement of the host immune system in the efficacy of combination therapy. It is possible that platinum may stimulate certain immune populations to secrete IFN, which acts on tumor cells to upregulate their IFN response. CONCLUSION Activation of the type I IFN response by eIF4A inhibition combined with platinum in vivo can lead to synthetic lethality of tumor cells. These studies not only offer novel insights into eIF4A biology but also provide valuable guidance for ongoing and future clinical trials. Citation Format: Na Zhao, Elena Kabotyanski, Alexander Saltzman, Jeffrey Rosen. Unexpected synthetic lethality mechanisms in eIF4A-targeted therapy abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B007.