We performed an unsupervised hierarchical clustering analysis based on expression levels of EMT signature genes ( 5, 9) and found that seven of the 37 gastric cancer cell lines exhibit robust EMT features ( Fig. Here, we have expanded this panel by adding eight additional gastric cancer cell lines, SNU5, SK-GT-2, IM95, MKN7, NUGC3, NUGC4, RERF-GC-1B, and SCH ( Supplementary Table 1). Previously, we classified a panel of 29 gastric cancer cell lines into intrinsic molecular subtypes by analyzing whole exome sequencing and RNA sequencing data ( 9). RESULTS Large-scale chemical screening identified small-molecule compounds selectively targeting EMT-subtype gastric cancer cell lines Hence, the findings from this study provide a novel precision drug candidate for further drug development. This study highlights the altered central energy metabolism as a synthetic lethal target pathway for the selective intervention of EMT-subtype gastric cancers. We further investigated the molecular targets and the underlying selectivity mechanisms of one of the hit compounds, YK-135. In the present study, we conducted a large-scale chemical screen using 37 gastric cancer cell lines and 48,467 synthetic small-molecule chemical compounds to identify novel drug candidates with selective cytotoxicity against EMT-subtype gastric cancer cell lines. Consequently, there are vital unmet needs that demand the development of new therapeutic interventions targeting the EMT-subtype gastric cancer to improve the survival outcomes of these patients. In addition, the rare druggable oncogenic mutations and low mutation burden of this subtype render targeted therapies and immunotherapies ineffective, respectively ( 7, 8). The EMT-subtype gastric cancers are also chemo-resistant due to their low proliferation rate ( 6). Later, the EMT-activated gastric cancer subtype was consistently found in diverse cohorts of gastric cancer ( 4- 6). Of these, the GS subtype is associated with epithelial-to-mesenchymal transition (EMT) features ( 2). The Cancer Genome Atlas (TCGA) project classified gastric cancers into four molecular subtypes: tumors positive for Epstein-Barr virus (EBV), chromosomal instable tumors, tumors with microsatellite instability (MSI), and genomically stable (GS) tumors. Advances in genomic technologies have enabled a better understanding of cancers by uncovering genetic heterogeneity that enabled molecular classifications ( 2- 5) which can affect prognosis and therapeutic outcomes in gastric cancer. Gastric cancer is the fifth most diagnosed cancer and the fourth leading cause of cancer-related mortality worldwide ( 1). Keywords: EMT, Gastric cancer, Glycolytic capacity, Mitochondrial complex I, OXPHOS These findings highlight mitochondrial complex I inhibitors as promising therapeutic agents for EMT-subtype gastric cancers and YK-135 as a novel chemical scaffold for further drug development.
Other well-known mitochondrial complex I inhibitors (e.g., rotenone and phenformin) mimic the efficacy of YK-135, supporting our results. We found that the lower glycolytic capacity of the EMT-subtype gastric cancer cells confers synthetic lethality to the inhibition of mitochondrial complex I, possibly by failing to maintain energy homeostasis. YK-135 exerts its cytotoxic effects by inhibiting mitochondrial complex I activity and inducing AMP-activated protein kinase (AMPK)-mediated apoptosis. We identified YK-135, a small-molecule compound that showed higher cytotoxicity toward EMT-subtype gastric cancer cell lines than toward non-EMT-subtype gastric cancer cell lines. Here, we conducted a high-throughput chemical screen using 37 gastric cancer cell lines and 48,467 synthetic smallmolecule compounds. Pharmacologically actionable somatic mutations are rarely found in EMT-subtype gastric cancers, limiting the utility of targeted therapies. ABSTRACT Epithelial-to-mesenchymal transition (EMT)-subtype gastric cancers have the worst prognosis due to their higher recurrence rate, higher probability of developing metastases and higher chemo-resistance compared to those of other molecular subtypes.
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