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27-09-2017 | Image

Box 2

Synthetic lethality is a useful approach to uncover biological mechanisms in both normal and cancerous cells, but the ultimate therapeutic goal is to add another weapon to the arsenal of personalized medicine. The synthetic lethal interaction of poly(ADP-ribose) polymerase (PARP) with the breast cancer susceptibility genes BRCA1 and BRCA2 was discovered by hypothesis-driven direct testing in 2005106,107. PARP inhibitors were first used in clinical trials as a synthetic lethal therapy in BRCA1/2 germline-mutated tumours in 2009108 and currently represent the only synthetic lethality strategy that has been approved for use in patients with cancer. As such, it is useful to review its journey from discovery to the clinic and to examine the challenges that may need to be addressed for other synthetic lethal targets that enter the clinic.