Targeting synthetic lethal paralogs in cancer

Synthetic lethal interactions, where mutation of one gene renders cells sensitive to inhibition of another gene, can be exploited for the development of targeted therapeutics in cancer. Pairs of duplicate genes (paralogs) often share common functionality and hence are a potentially rich source of synthetic lethal interac-tions. Because the majority of human genes have paralogs, exploiting such inter-actions could be a widely applicable approach for targeting gene loss in cancer. Moreover, existing small-molecule drugs may exploit synthetic lethal interac-tions by inhibiting multiple paralogs simultaneously. Consequently, the identifi-cation of synthetic lethal interactions between paralogs could be extremely informative for drug development. Here we review approaches to identify such interactions and discuss some of the challenges of exploiting them.