Genetic and epigenetic changes (e.g., histone methylation) contribute to cancer development and progression, but our understanding of whether and how specific mutations affect a cancer's sensitivity to histone demethylase (KDM) inhibitors is limited. Here, we evaluated the effects of a panel of KDM inhibitors on lung adenocarcinomas (LuAC) with various mutations. Notably, LuAC lines harboring KRAS mutations showed hypersensitivity to the histone H3K27 demethylase inhibitor GSK-J4. Specifically, GSK-J4 treatment of KRAS mutant-containing LuAC downregulated cell-cycle progression genes with increased H3K27me3. In addition, GSK-J4 upregulated expression of genes involved in glutamine/glutamate transport and metabolism. In line with this, GSK-J4 reduced cellular levels of glutamate, a key source of the TCA cycle intermediate α-ketoglutarate (αKG) and of the antioxidant glutathione, leading to reduced cell viability. Supplementation with an αKG analogue or glutathione protected KRAS-mutant LuAC cells from GSK-J4-mediated reductions in viability, suggesting GSK-J4 exerts its anticancer effects by inducing metabolic and oxidative stress. Importantly, KRAS knockdown in mutant LuAC lines prevented GSK-J4-induced decrease in glutamate levels and reduced their susceptibility to GSK-J4, whereas overexpression of oncogenic KRAS in wild-type LuAC lines sensitized them to GSK-J4. Collectively, our study uncovers a novel association between a genetic mutation and KDM inhibitor sensitivity and identifies the underlying mechanisms. This suggests GSK-J4 as a potential treatment option for cancer patients with KRAS mutations. SIGNIFICANCE: This study not only provides a novel association between KRAS mutation and GSK-J4 sensitivity but also demonstrates the underlying mechanisms, suggesting a potential use of GSK-J4 in cancer patients with KRAS mutations.

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