Figure 2. Conceptual framework for optimized prioritization of synthetic lethal therapeutic approaches.

Germane to the successful translation of synthetic lethal interactions into cancer treatments is the consideration of characteristics of the gene altered in the cancer cells including whether its loss is mono- or bi-allelic or biologically sufficient to cause a phenotype in the context of a synthetic lethal interaction, the prevalence of its loss in a given cancer type or across cancers and whether the loss of the gene is essential for tumor development and/or maintenance. The features of the target gene (i.e. gene to be inhibited therapeutically) also need to be considered, included its expression in the cell lineage and/or cancer type of interest and the toxicity impact of its inhibition. The characteristics of the synthetic lethal interaction itself also need to be considered, including the effect size (magnitude of the therapeutic index in preclinical models) and penetrance. Synthetic lethal interactions may be limited to a specific genetic context or tissue type/lineage; assessing the penetrance of the genetic interaction across varying model systems and cell lineages can inform the robustness of the therapeutic window.