Background: As the most lethal neuroendocrine tumor, small cell lung cancer (SCLC) can drive its progression by hijacking neuronal mechanisms. At the core of this neural integration is the N-methyl-D-aspartate receptor (NMDAR) complex. However, its pan-cancer expression and clinical significance in SCLC remain poorly understood. Methods: We characterized NMDAR transcriptomic profiles across human cancers to develop the NMDAscore, and analyzed three independent European and Asian SCLC cohorts to identify prognostic biomarkers. Furthermore, we investigated the molecular mechanisms of GRIN2A and evaluated the efficacy of GluN2 inhibitors. Results: The developed NMDAscore exhibited significant prognostic correlations in ACC, COAD, KIRC, UVM, KIRP, OV, PCPG, UCS, THCA, THYM, HNSC, KICH, LGG, and PAAD. Focusing on the SCLC cohorts, we identified GRIN2A (encoding the GluN2A subunit) as a statistically relevant prognostic biomarker associated with poor survival. Mechanistically, GRIN2A upregulation correlates with the activation of neuro-synaptic signaling, metabolic reprogramming, genomic instability, and an immune-cold microenvironment characterized by CD8+ T cell exclusion. Pharmacological inhibition of GluN2 using dizocilpine and the FDA-approved antagonist memantine suppressed SCLC proliferation and tumorigenicity in vitro, in 3D tumor spheroids and in vivo xenograft models. Conclusions: Collectively, these findings establish GRIN2A as a prognostic biomarker, linking synaptic hijacking, metabolic plasticity, immune evasion, and drug resistance, and identify the therapeutic potentials of the GluN2 inhibitors dizocilpine and memantine for SCLC.
Zhang et al. (Mon,) studied this question.
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