Induction of pancreatic tumor-selective ferroptosis through modulation of cystine import

摘要: Abstract Pancreatic ductal adenocarcinoma (PDA) is the third-leading cause of cancer mortality in US and highly resistant to classical, targeted, immune therapies. We show that human PDA cells are dependent on provision exogenous cystine avert a catastrophic accumulation lipid reactive oxygen species (ROS) that, left unchecked, leads ferroptotic cell death, both vitro vivo. Using dual-recombinase genetically engineered model, we found acute deletion Slc7a11 led tumor-selective ferroptosis, tumor stabilizations/regressions, extended overall survival. The mechanism ferroptosis induction required concerted depletion glutathione coenzyme A, highlighting novel branch ferroptosis-relevant metabolism. Finally, vivo using pre-IND agent cyst(e)inase phenocopied deletion, inducing disease stabilizations/regressions well-validated KPC model PDA. One Sentence Summary Genetic pharmacological targeting import induces pancreatic cancer-selective