Epigenetic synthetic lethality as a cancer therapeutic strategy: synergy of experimental and computational approaches

Cancer treatment is an ongoing challenge, as directly targeting oncogenic drivers is often unfeasible in many patients due to the lack of druggable targets. This has led to the exploration of alternative strategies, such as exploiting synthetic lethality (SL) relationships between genes. SL facilitates the indirect targeting of oncogenic drivers, as exemplified by the clinical success of PARP inhibitors against BRCA-mutated tumors. Advances in high-throughput perturbation screens and multi-omics technologies have deepened our understanding of SL relationships, while computational models enhance SL predictions to better reflect biological complexity. However, while numerous experimental and computational methods have been developed to identify SL interactions, difficulties remain in translating these findings into clinical applications. This review combines recent progress on SL relationships in cancer with emerging insights into epigenetic regulation, highlighting how epigenetic drugs (epidrugs) can provide new opportunities for targeted interventions, offering a way to minimize off-target effects and enhance therapeutic precision. To advance SL-based therapies, efforts must focus not only on identifying new SL interactions but also on consolidating existing knowledge and integrating experimental and computational approaches to characterize the vulnerabilities of cancer cells. Strengthening this foundation will be critical for the effective development of SL-based cancer treatments. Synthetic Lethality (SL) describes a relationship between a pair of genes where cells remain viable if at least one gene of the pair functions normally, but die if both genes are altered (e.g. mutated) at the same time. These alterations may occur naturally or can be drug-induced. Genes are often mutated in cancer cells, so therapeutically altering the SL partner of a gene already mutated in the cancer cells leads to cell death, as both partner genes are now altered, while normal cells lacking the initial mutation are spared. As gene function can be affected by diverse alterations besides DNA mutations, the mechanisms that control gene regulation without changing the DNA sequence, referred to as epigenetics, also need to be considered. In this Perspective, we highlight the importance of integrating both genetic and epigenetic alterations while studying SL relationships, and we explore how these SL relationships can be better identified by integrating experimental and computational approaches, to understand gene-gene interactions in order to broaden the treatment possibilities.