Abstract 6047: ZFTA-RELA fusion aberrantly drives glutamine metabolism in lethal pediatric ependymomas

Abstract

Abstract Ependymomas are fatal brain malignancies with very few treatment options. More than 70% of supratentorial (ST) ependymomas harbor fusions of the zinc-finger containing, chromatin modifier ZFTA and the transcriptional activator of NF-κB signaling, RELA. Oncogene-driven metabolic reprogramming is a fundamental hallmark of cancer that enables sustained tumor proliferation. ZFTA-RELA fusion protein is essential for tumorigenesis and our goal is to determine how it drives metabolism in ST-ependymomas. To address this, we developed an in vitro isogenic system by expressing the ZFTA-RELA fusion protein in immortalized mouse neural stem cells (ZFTA-RELAFUS). Using this system, we show that these tumor cells selectively upregulate expression of the glutamine transporter (SLC1A5), glutaminase (GLS), and many downstream enzymes in the glutamine metabolic pathway. Therefore, we hypothesized that the ZFTA-RELA fusion drives glutamine metabolism in ST-ependymomas. We further demonstrate that ZFTA-RELAFUS tumor cells utilize glutamine to maintain redox homeostasis and show marked cell death upon its withdrawal. Moreover, JHU-083, a specific pharmacologic inhibitor of glutaminase, killed ZFTA-RELAFUS tumor cells in vitro and in vivo. To summarize, our results suggest that the ZFTA-RELA fusion expressing tumor cells exhibit strong glutamine dependence, and targeting it has significant therapeutic relevance. Citation Format: Siva Kumar Natarajan, James Haggerty-Skeans, Joanna Lum, Pranav Narayanan, Stefan Sweha, Sushanth Sunil, Pooja Panwalkar, Jill Bayliss, Peter Sajjakulnukit, Derek Dang, Abhinav Achreja, Deepak Nagrath, Costas Lyssiotis, Sriram Venneti. ZFTA-RELA fusion aberrantly drives glutamine metabolism in lethal pediatric ependymomas [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 6047.