A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene Ji Luo,1 Michael J. Emanuele,1 Danan Li,2 Chad J. Creighton,3 Michael R. Schlabach,1 Thomas F. Westbrook,4 Kwok-Kin Wong,2 and Stephen J. Elledge1,* 1Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women’s Hospital 2Department of Medicine, Harvard Medical School and Department of Medical Oncology, Dana Farber Cancer Center, Ludwig Center at Dana-Farber/Harvard Cancer Center Boston, MA 02115, USA 3Dan L. Duncan Cancer Center Division of Biostatistics 4Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Human Genetics, Dan L. Duncan Cancer Center Baylor College of Medicine, Houston, TX 77030, USA *Correspondence:
[email protected] DOI 10.1016/j.cell.2009.05.006 SUMMARY (Ngo et al., 2006; Schlabach et al., 2008; Silva et al., 2008). We have developed barcoded, retroviral/lentiviral-based short Oncogenic mutations in the small GTPase Ras are hairpin RNA (shRNA) libraries targeting the entire human genome highly prevalent in cancer, but an understanding of to enable genome-wide loss-of-function analysis through stable the vulnerabilities of these cancers is lacking. We gene knockdown (Silva et al., 2005). Our design also allowed undertook a genome-wide RNAi screen to identify us to use microarray deconvolution to develop a multiplex synthetic lethal interactions with the KRAS onco- screening platform that enables the highly parallel screening gene. We discovered a diverse set of proteins whose of >10,000 shRNAs in a pool-based format (Schlabach et al., 2008; Silva et al., 2008).