Abstract 4678: Identifying and exploiting a novel role of FTO in promoting cysteine metabolism for NSCLC therapy

Abstract The RNA demethylase enzyme FTO is emerging as an important oncogenic factor and therapeutic target in a variety of solid tumors. However, its effect on cancer metabolism remains largely unknown. Here we show that FTO promotes cysteine metabolism, a hallmark of metabolic rewiring in non-small cell lung cancer (NSCLC) cells. Mechanistically, FTO inhibition reduces the expression of multiple targets in the cysteine metabolism pathway including the cystine transporter SLC7A11 involved in exogenous cystine uptake as well as two key enzymes cystathionine β-synthetase (CBS) and cystathionine γ-lyase (CTH) involved in de novo cysteine synthesis. Functionally, FTO inhibition reduces cystine uptake and NSCLC growth and survival in a homocysteine-dependent manner. As cysteine plays a crucial role in glutathione biosynthesis and maintenance of cellular redox homeostasis, FTO inhibition decreased glutathione levels and increased reactive oxygen species (ROS) levels in NSCLC cells. To therapeutically exploit the increased oxidative stress in NSCLC cells treated with FTO inhibitors, we combined FTO inhibition with radiation therapy. FTO inhibition enhanced the radiosensitivity of NSCLC cells. Our findings reveal a novel role for FTO in NSCLC cysteine metabolism and oxidative stress, highlighting the therapeutic potential of FTO inhibition as a strategy to enhance the efficacy of radiation therapy for the treatment of NSCLC. Citation Format: Nishanth Kuganesan, Stavros Melemenidis, Edward E. Graves, Erinn B. Rankin. Identifying and exploiting a novel role of FTO in promoting cysteine metabolism for NSCLC therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4678.