Genome-wide RNAi profiling to determine contexts of vulnerability in cancer cells

C53

RNA interference has emerged as a powerful functional genomics technology to perform targeted gene knockdowns and study loss-of-function phenotypes. This has been exploited in various drug discovery and development applications, including target characterization and validation. The availability of reagent libraries has paved the way for genome-wide high throughput screens that have been recently reported by several groups. Here, we report a genome-wide loss-of-function siRNA screen of druggable targets (~7000 genes) in 4 cell lines representing different tumor types and genetic backgrounds. Assay development, validation, primary and confirmation screens were all done using a cell viability readout. Statistical approaches along with integrative analyses of orthogonal datasets (arrayCGH, mutation, expression) were employed to identify ‘essential’ or ‘survival’ genes that upon knockdown caused significant loss of viability in a general or cell-specific context. Wherever possible, genomics data from primary tumor samples has been leveraged to establish clinical relevance. A few examples will be shown and discussed. These ‘contexts of vulnerability/lethality’ provide valuable data in understanding target or pathway dependence and functional consequences. Pending further follow up, these findings are likely to shed light on new targets as well as the development strategy for targeted agents.