The term synthetic lethality was first used in 1922 by C.Bridges1 to describe events where two non-lethal mutations are brought together in combination to cause cell death. Synthetic lethality offers significant potential in the field of cancer research, with many groups focusing on the selective inhibition of target proteins that are lethal to only those cells harboring a mutated cancer gene.
A number of siRNA and shRNA screens have identified targets that exhibit differential dependencies between KRAS mutant and KRAS wild-type tumours, but there is poor overlap between these published studies. Next generation screens that exploit both isogenic cell lines and cancer cell panels, and use a combination of knockdown (si/shRNA) and knock-out (CRISPR-Cas9-sgRNA) methodologies might be more effective at identifying novel targets that withstand validation. However, if we are to detect co-dependence as well as synthetic lethal interactions, screens must be performed under conditions where mutant KRAS alleles are essential for growth.