Abstract 2085: Targeting the translation initiation complex component eIF4G1 in melanoma

Abstract The translation initiation factor 4F (eIF4F) complex assembly is a rate-limiting step in mRNA translation. eIF4F subunits including eIF4A, eIF4E, and eIF4G, are often upregulated in cancer and neurodegeneration diseases. Elevated eIF4F level/activity has been correlated with poor prognosis and drug resistance. Leveraging our findings with the small molecule SBI-756, which interacts with eIF4G1 and impairs eIF4F complex assembly, we set to map domains that are required for SBI-756 activity. A CRISPR screen using sgRNAs that target different sequences on eIF4G1 led to the identification of the MA3 domain, as a putative binding site for SBI-756. Deletion/mutation of the eIF4G1 MA3 domain attenuated melanoma cells and spheroids growth. Polysome profiling assays confirmed attenuated translation activity, which resembled those seen with SBI-756. In silico virtual screen identified 64 small molecules (out of >10 million) that interact with the MA3 domain. Of these, we have selected four that effectively attenuated melanoma growth in culture. Analogs developed for these four compounds were more potent in impairing the assembly of the eIF4F complex, inhibition of protein translation and the 2D and 3D growth of melanoma cells. RNA-sequencing analysis highlighted altered expression of genes implicated in apoptosis, UPR, cell cycle, and ROS pathways, leading us to test possible combination with pathways that may complement the above. Among those, autophagy inhibitors synergized with our lead compound, M19-6, resulting in efficient melanoma cell death, using notably lower concentrations of these inhibitors. Our findings identify the eIF4G1 MA3 domain as an important player in eIF4F assembly and a potential target for cancer therapy. Citation Format: Yongmei Feng, Mariia Radaeva, Hyungsoo Kim, Anagha Deshpande, Ani Deshpande, Predrag Jovanovic, Rabi Murad, Ivan Topisirovic, Steven Olson, Artem Cherkasov, Ze'ev Ronai. Targeting the translation initiation complex component eIF4G1 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2085.