Genetic interactions, including synthetic lethal effects, can now be systematically identified in cancer cell lines using high-throughput genetic perturbation screens. Despite this advance, few genetic interactions have been reproduced across multiple studies and many appear highly context-specific. Here, by developing a new computational approach, we identified 220 robust driver-gene associated genetic interactions that can be reproduced across independent experiments and across non-overlapping cell line panels. Analysis of these interactions demonstrated that: (i) oncogene addiction effects are more robust than oncogene-related synthetic lethal effects; and (ii) robust genetic interactions are enriched among gene pairs whose protein products physically interact. Exploiting the latter observation, we used a protein–protein interaction network to identify robust synthetic lethal effects associated with passenger gene alterations and validated two new synthetic lethal effects. Our results suggest that protein–protein interaction networks can be used to prioritise therapeutic targets that will be more robust to tumour heterogeneity.