Abstract 4655: Identification of non-small cell lung cancer metabolic subtypes and targeting glucose pathway

Abstract Background- NSCLC accounts for approximately 80% of all lung cancer cases. Despite significant treatment efforts, overall survival rates for NSCLC patients remain low. The NSCLC microenvironment and metabolism are also not fully understood, prompting ongoing research to better understand lung cancer progression and metastasis. To address tumor heterogeneity and define precise metabolic clusters, we applied non-negative matrix factorization (NMF) and discovered that the NMF clusters were significantly associated with clinical outcomes (progression, survival). Method- To investigate metabolic functions in 73 patients who received immunotherapy, we performed NMF clustering to identify subgroups based on significantly differentially expressed genes from NanoString data. After performing NMF, we found 5 subgroups then defined the metabolic function of each cluster using Gene Set Variation Analysis (GSVA) and identified the top 10 marker genes for each cluster using the Wilcoxon test from the Seurat package. Result- We found that clusters 1 and 2 had a higher proportion of immune cells compared to other clusters. Interestingly, while cluster 3 showed a higher proportion of immune cells, it had a lower overall survival rate and progression-free survival rate compared to cluster 1. We identified the key difference between these two clusters as glucose uptake. Moreover, glucose-related genes (SLC2A1, SLC2A3, SLC2A6, SLC2A14, SLC2A8, and SLC2A5) were highly expressed in cluster 2, which exhibited a higher proportion of Tregs and a stronger correlation between the glucose transport pathway and Tregs. Additionally, we found that SLC2A3 expression was significantly associated with overall survival and progression-free survival. To validate our findings and demonstrate their robustness, we corroborated them using GSE161537 data. This study may help identify metabolic pathways and biomarkers that could be targeted in precision oncology. Citation Format: Seo-Young Lee, Youngjoo Lee, Park Seog Yun, Beom K Choi, Sohyun Park, Jaemin Kim. Identification of non-small cell lung cancer metabolic subtypes and targeting glucose pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4655.