Differential Sensitivity to xCT-inhibition by ME1 expression.

Many cancers overexpress malic enzyme 1 (ME1), an enzyme essential in redox homeostasis through the generation of cytoplasmic NADPH. While ME1 overexpression is correlated with aggressive cancer phenotypes, little is known about the metabolic consequences of ME1 absence, recently identified as characteristic of synovial sarcoma. ACXT-3102 is a novel, dual-domain therapeutic produced by the conjugation of erastin, a small molecule xCT-inhibitor, and sigma-2 ligand, shown to induce ROS-dependent cell death in various cancer models. This study examines ME1 absence as a marker of sensitivity to xCT-inhibition in multiple malignancies and its role as a potential therapeutic marker for ACXT-3102 treatment. ME1-expressing and non-expressing tumor cell lines were identified and matched ME1 knockdown (KD) and overexpressing (OE) lines were created. Sensitivity to ACXT-3102 treatment was investigated in various tumor lines in vitro and in vivo. ME1 absence is identified in a subset of multiple malignancies. ME1 KD increases ME1-expressing tumor cell sensitivity to ACXT-3102, while ME1 re-introduction decreases xCT-inhibition sensitivity in ME1-null lines in in vitro and in vivo models. Compared to ME1-expressing cancers, ME1 absence increases tumor sensitivity to xCT inhibition. Our findings suggest ME1-null and low-expressing tumors constitute a distinct subset across multiple solid tumor types, representing a potential metabolic vulnerability. Given this differential sensitivity, ME1 deficiency may serve as a promising biomarker for selecting patients likely to benefit from xCT-targeting therapies. These results support further investigation into ME1 expression as a predictive tool for clinical trial stratification and of xCT-inhibition treatment strategies.