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26-06-2017 | PARP inhibitors | Article

Synthetic lethality and cancer

Nigel J O'Neill, Melanie L Bailey, Philip Hieter


A synthetic lethal interaction occurs between two genes when the perturbation of either gene alone is viable but the perturbation of both genes simultaneously results in the loss of viability. Key to exploiting synthetic lethality in cancer treatment are the identification and the mechanistic characterization of robust synthetic lethal genetic interactions. Advances in next-generation sequencing technologies are enabling the identification of hundreds of tumour-specific mutations and alterations in gene expression that could be targeted by a synthetic lethality approach. The translation of synthetic lethality to therapy will be assisted by the synthesis of genetic interaction data from model organisms, tumour genomes and human cell lines.

Nat Rev Gen 2017;18:613–623. doi:10.1038/nrg.2017.47

Advances in genome sequencing are driving a paradigm shift in cancer treatment1: it is now possible to rapidly identify genetic and epigenetic changes that differentiate tumour cells from non-tumour cells in a patient. Tumour-specific genetic alterations reveal not only the biological changes that drive tumour progression but also the vulnerabilities that can be exploited to selectively target the tumour with therapeutics. Personalized (or precision) genotype-targeted cancer treatment has the potential to offer individualized, highly specific therapies with fewer adverse effects, as well as to reduce the overtreatment of tumours. Indeed, personalized oncogenomic approaches are currently being adopted on the front lines of cancer care and have had success in the treatment of patients with tumours that have failed to respond to standard therapies2, 3, 4.

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