Abstract 3719: Targeting the eIF6 and 60S ribosomal subunit interaction interface in cancers

Abstract

Abstract Translational control is integral to cancer initiation and progression. A subset of translation initiation factors are deregulated in cancers to facilitate their rampant growth and proliferation. Eukaryotic translation initiation factor 6 (eIF6) is one such factor 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 complex. 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 extensive 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. 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. Future studies will determine the mRNA targets that are translationally deregulated by inactivation of eIF6. We will also determine the effect of targeting eIF6 function in inhibiting tumor growth and progression in vivo. Citation Format: Kavya Meena Harish, Aparna Biswas, Poonam Roshan, Sofia Origanti. Targeting the eIF6 and 60S ribosomal subunit interaction interface in cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3719.