Figure 1. Synthetic lethality: definition and approaches for the identification of synthetic lethal interactions.

A) Synthetic lethality is defined by cellular or organismal lethality caused by combined alterations of gene pairs that are otherwise individually viable. A commonly employed and therapeutically relevant definition encompasses pharmacologic inhibition of one gene product with genetic inactivation of the other. B) Identification of SL drug targets has been facilitated by high-throughput genetic and chemogenetic screening in human cancer cell lines. The use of isogenic models in forward CRISPR-based screens minimizes potential confounding by co-occurring genetic alterations and facilitates attribution of a cellular phenotype to a specific SL pair. Chemogenetic screens appear to be particularly efficacious in developing new patient-selection hypotheses for compounds with known mechanism-of-action (9,113–116) or to uncover potential mechanisms of resistance (117,118). C) Overview of the Cancer Dependency Map (DepMaP) a large-scale multi-institution functional genomics project aimed at creating a comprehensive database of potential novel drug targets and biomarkers across cancer types. A recent integrated analysis of CRISPR-based screens from the Cancer Dep Map effort identified >1000 candidate genetic dependencies across 786 cell lines representing 42 cancer types (119). Abbreviations: KO, knocked out; WT, wild-type; RPPA, reverse phase protein array; FDR, false discovery rate; GDSC, Genomics of Drug Sensitivity in Cancer; PRISM, Profiling Relative Inhibition Simultaneously in Mixtures; CTRP, Cancer Therapeutics Response Portal.