Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage)1. Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells2. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress3,4,5.
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We thank K. Chu, L. Brown-Endres, E. Lerner and F. Neville for their help in preparing the manuscript, W. C. Hahn for BJ cell lines, V. Band for 76N cells, D. Beer for H1975 cells and K. Todorova, G. Wei, S. Ong, S. Norton and F. An for technical assistance. This project has been supported in part by grants CA142805, CA127247, CA085681 and CA080058 from NIH. This research was supported by the National Cancer Institute’s Initiative for Chemical Genetics Contract (N01-CO-12400) and Cancer Target Discovery and Development Network grant (5 RC2 CA148399-02), as well as the National Institutes of Health Genomics Based Drug Discovery—Target ID Project Grant (RL1HG004671, which is administratively linked to National Institutes of Health Grants RL1CA133834, RL1GM084437 and UL1RR024924). S.L.S. is an Investigator with the Howard Hughes Medical Institute.
The file contains Supplementary Methods, Supplementary Tables 1-2, Supplementary Figures 1-33 with legends and additional references.