P-OGC32 Copper-dependent cell death is a cancer specific vulnerability in oesophageal adenocarcinoma and provides the opportunity for future biomarker-stratified clinical trials

Abstract Background Oesophageal adenocarcinoma (OAC) is of increasing global concern due to incidence, lack effective treatments, and poor prognosis. Therapeutic target discovery clinical trials have been hindered by the heterogeneity disease, dominance large-scale genomic rearrangements, driver mutations. We profiled small-molecule compounds using an innovative high content imaging assay in a panel transformed non-transformed oesophageal cell lines identify OAC-specific cytotoxic compounds, new therapeutic targets, potential drug repurposing opportunities, chemical starting points for treatment OAC. Methods comprehensively 19,555 quantify 1000’s subcellular features capture important phenotypes missed standard approaches. Prioritised molecules then underwent functional, transcriptomic, metabolomic characterisation across panels patient-derived organoids identification mechanisms. Results identified 72 lead as exhibiting cytotoxicity characterised three most potent selective depth, each different proposed classes structures. Using several orthogonal methods we uncovered unified mechanism action targetable vulnerability OAC involving copper-dependent death. Strikingly no phenotypic effects or changes gene-expression were observed following with these normal gastric providing support this cancer-specific phenomenon. Conclusions applied imaging, transcriptomic analyses reveal unique defined death highly compounds. Finally, through integration metabolomics gained insight into sensitivity provide basis future biomarker-stratified trial drugs