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. Full payment is due four weeks prior to the meeting.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. No-Housing packages include all costs except housing. Regular packages are all-inclusive and cover registration, food, housing, parking, a wine-and-cheese party, cocktail reception, and lobster banquet. We look forward to seeing you at Cold Spring Harbor in April. Apply in writing to Maureen Morrow stating need for financial support - preference is given to those submitting abstracts. We have applied for funds from industry to partially support graduate students and postdocs. We are eager to have as many young people as possible to attend since they are likely to benefit most from this meeting. Status (talk/poster) of abstracts will be posted on our web site as soon as decisions have been made by the organizers. Selection of material for oral and poster presentation will be made by the organizers and individual session chairs. They should contain only new and unpublished material and must be submitted electronically by the abstract deadline. Melissa Moore, University of Massachusetts Medical SchoolĪbstracts are welcomed on all scientific topics related to the development of RNA and other oligonucleotide-based therapeutic approaches. Single & Double Stranded Therapeutic OligonucleotidesÄavid Corey, UT Southwestern Medical CenterĪdrian Krainer, Cold Spring Harbor Laboratory We are pleased to announce the fourth Cold Spring Harbor conference on RNA and Oligonucleotide Therapeutics, which will begin at 7:30 pm on Wednesday April 8 and run through lunch on Saturday, April 11, 2015. Laura Sepp-Lorenzino, Alnylam Pharmaceuticals Bruce Sullenger, Duke University Annemieke Aartsma-Rus, Leiden University Medical Center Arthur Krieg, Checkmate Pharmaceuticals
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