Fig. 3.

Considerations when validating synthetic lethal targets. Several factors should be considered when deciding whether or not to translate a synthetic lethal discovery to therapeutics. If the target was discovered from an RNAi screen, off-target effects should be eliminated by testing individual siRNA duplexes, using pools of siRNAs, or even testing the interaction using small molecules if available (a). Secondly, the synthetic lethality should be verified in a panel of cell lines for the indication(s) of interest to assess potential applications of the therapeutic strategy of interest (b). The therapeutic window should also be assessed to ensure that synthetic lethality occurs in a cancer-specific manner (c). When developing pharmaceuticals for the target of interest, it is crucial to understand whether it is the enzymatic activity or a specific interaction that is responsible for the synthetic lethality observed (d). Finally, synthetic lethality might be dependent on the extent of genetic alteration. This dose dependency should be explored and addressed when designing and developing therapeutics for synthetic lethal targets (e)