Ephrins/eph as novel synthetic lethal targets in Kras-mutant colorectal cancer

e13578 Background: Mutations in the Kras proto-oncogene are found in 40%-45% of colorectal cancer (CRC) patients and occur mainly in codon 12 and 13. Kras mutant (MT) CRC tumours are resistant to EGFR mAb therapies. Clear understanding of the biology of KrasMT CRC is important, and identification of druggable targets uniquely required by KrasMT CRC tumours has the potential to fill a gap in the therapeutic armamentarium of advanced CRC. The aim of this study was to identify novel targets whose knock-down is synthetically lethal with Kras mutation in CRC models. Methods: Transcriptional profiling (Almac Diagnostics CRC DSA) of primary KrasMT and WT CRC tissues and paired KrasMT and WT CRC xenografts models was performed and Metacore pathway analysis was used to identify individual genes from novel Kras-dependent pathways for incorporation into a primary RNAi screen. Results: Using clinical and in vivo KrasMT/WT CRC samples and public available Kras signatures, we identified 30 signalling pathways and 160 g...