Effective targeted therapies for small cell lung cancer (SCLC) remain a significant challenge. Targeting the epigenome to overcome immune evasion and chemoresistance represents a promising strategy to improve treatment outcomes. In this study, we explored the role of Polycomb repressive complex 2 (PRC2), a key transcriptional repressor, by dissecting its structural and enzymatic functions. Conditional deletion of Eed, a core structural component of PRC2, prevented tumor formation in an autochthonous SCLC model. In contrast, enzymatic inhibition of EZH2 had no impact on tumor growth but significantly altered the PRC2 interactome, unveiling novel targets for drug development. Since EZH2 inhibitors are already clinically approved for other cancers, we conducted a focused combination drug screen to enhance their therapeutic potential in SCLC. Our findings revealed that prolonged EZH2 inhibition sensitized neuroendocrine cancer cells to G9a/GLP inhibition. Transcriptomic analysis revealed that the drug combination triggered an oxidative stress response by modulating the expression of cellular oxidases, an effect that could be reversed by antioxidant treatment. These results underscore the critical role of PRC2's structural functions in SCLC and identify promising drug combinations to enhance the efficacy of EZH2 inhibitors.
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