Lipid rafts are highly ordered membrane domains rich in cholesterol and sphingolipids that provide a scaffold for signal transduction proteins; altered raft structure has also been implicated in cancer progression. We have shown that 25 M 10-(octyloxy) decyl-2-(trimethylammonium) ethyl phosphate (ODPC), an alkylphospholipid, targets high cholesterol domains in model membranes and induces apoptosis in leukemia cells but spares normal hematopoietic and epithelial cells under the same conditions. We performed a quantitative ( The development of resistance to drugs that inhibit signaling pathways in cancer cells has emerged as a major limitation of targeted therapy. While the major mechanism of acquired resistance is the emergence of additional mutations or growth factor receptor overexpression (1), recent studies have shown an interesting mechanism of constitutional resistance to epidermal growth factor receptor inhibitors in breast cancer cells, which involves structural alterations in lipid rafts and is independent of the kinase itself (2).Lipid rafts or membrane rafts are highly ordered membrane domains that are rich in cholesterol and sphingolipids which function by compartmentalizing diverse cellular processes (3, 4), including signal transduction (5-7). Emerging evidence associates altered raft structure with cancer progression (8 -10). Therefore, the development of therapeutic strategies for disrupting raft-based cell signaling in cancer represents a potentially useful approach. We and others have presented evidence that alkylphospholipid (APL) 1 drugs target raft structure in leuFrom the ‡Instituto Nacional