A targetable FTO/SLC7A11/CBS/CTH axis controls cysteine metabolism, growth and survival in NSCLC.

Abstract

Cysteine metabolism plays a crucial role in the growth and survival of non-small cell lung cancer (NSCLC), although the mechanisms governing its regulation are not fully understood. Here, we demonstrate that the RNA demethylase FTO is a therapeutic target that drives cysteine metabolism in NSCLC cells. Genetic or pharmacologic inhibition of FTO reduced cystine uptake and transsulfuration activity, leading to depleted intracellular glutathione, elevated reactive oxygen species (ROS), and ROS-mediated DNA damage and cell death. Mechanistically, FTO promotes the expression of the cystine uptake transporter SLC7A11 and the transsulfuration enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH) to promote NSCLC cystine uptake, transsulfuration activity, and survival. FTO inhibition increased lipid peroxidation, reduced tumor growth, and resulted in additive therapeutic benefit in combination with radiotherapy in multiple NSCLC xenograft models. Collectively, our study reveals a role for FTO in cysteine metabolism and highlights the therapeutic potential of targeting cancer epitranscriptomics and cysteine metabolism for NSCLC therapy.