Exploring Context-specific Genetic Vulnerabilities in Human Cancer Cell Lines

Synthetic lethality arises when a combination of mutations in multiple genes leads to cell death, whereas a mutation in only one of them retains cell viability. This genetic concept is exploited for identification of targetable vulnerabilities in cancer. We developed a correlation network based on gene essentiality profiles derived from lentiviral-based genome-wide RNA interference screens across a panel of cancer cell lines from several tissues. Novel context-specific vulnerabilities were predicted from the network and further validated. For example, we found that sensitivity to mitochondrial oxidative phosphorylation inhibition varies amongst ovarian cancer cell lines. We also predicted varying sensitivity against alpha-ketoglutarate dehydrogenase inhibition in breast cancer cell lines. In addition, we identified exonuclease 1 as a sensitizing target in ovarian cancer cell lines expressing wild-type p53. Our findings suggest that our correlation network from functional genetic screens is predictive of context-specific vulnerabilities in cancer cells that help discovery of therapeutic strategies.M.Sc