Abstract 7078: Targeting eIF6 to modulate ribosomal subunit association dynamics in cancers

Abstract

Abstract Deregulation of ribosomal subunit levels and accessibility are hallmarks of cancer. Eukaryotic translation initiation factor 6 (eIF6) is a key regulator of ribosomal subunit association that is over expressed in many cancers including lung, colon, ovarian and breast cancers, and deregulation of eIF6 is correlated with a poor cancer prognosis. Association of eIF6 with 60S is critical for 60S assembly. However, eIF6 must be released from 60S prior to translation to permit inter subunit interactions between 60S and 40S and to facilitate the formation of translationally proficient 80S monosome. Release of eIF6 is deregulated in the ribosomopathy- Shwachman Diamond Syndrome that is predisposed to leukemias. Also, loss of eIF6 markedly delays tumorigenesis without affecting normal growth, which presents eIF6 as a viable therapeutic target. A potential therapeutic strategy is to target the eIF6 and 60S ribosomal interaction interface. Through biophysical analyses we had identified residues that are critical for the interaction between eIF6 and 60S ribosomal subunit. We show that targeting these key residues in the eIF6-60S interaction interface markedly delays colonic cancer growth and inhibits protein synthesis. Furthermore, we show that the levels of other eIFs and the release factors: SBDS, and EFL1-GTPase are unaltered in the mutant cells suggesting that the translational inhibition is primarily attributed to the deregulation of eIF6. Interestingly, targeting eIF6 leads to an upregulation of p53 independent of the DNA damage response, suggesting that ribosomal stress contributes to the stabilization of p53. Previously, it was shown that translation of Cdc42 was upregulated by eIF6 to promote invasiveness. However, Cdc42 levels were unaltered in the mutant cells. Future studies will determine the mRNA substrates that are translationally deregulated in the mutants. We will also determine the effect of disrupting eIF6 function in inhibiting tumor growth and progression in vivo. Category: MCB, Subcategory: MCB07-Gene regulation sub classification: Translational Control Citation Format: Kavya Meena Harish, Poonam Roshan, Aparna Biswas, Stella Anagnos, Riley Luebbers, Sofia Origanti. Targeting eIF6 to modulate ribosomal subunit association dynamics in cancers [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 7078.