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The great majority of targeted anticancer drugs inhibit mutated oncogenes that display increased activity. Yet many tumors do not contain such actionable aberrations, such as those harboring loss-of-function mutations. The notion of targeting synthetic lethal vulnerabilities in cancer cells has provided an alternative approach to exploiting more of the genetic and epigenetic changes acquired during tumorigenesis. Here, we review synthetic lethality as a therapeutic concept that exploits the inherent differences between normal cells and cancer cells. Furthermore, we provide an overview of the screening approaches that can be used to identify synthetic lethal interactions in human cells and present several recently identified interactions that may be pharmacologically exploited. Finally, we indicate some of the challenges of translating synthetic lethal interactions into the clinic and how these may be overcome.

Original publication

DOI

10.1146/annurev-pharmtox-010814-124511

Type

Journal article

Journal

Annu Rev Pharmacol Toxicol

Publication Date

2015

Volume

55

Pages

513 - 531

Keywords

clinical translation, drugs, genetic screens, synthetic lethality, Animals, Antineoplastic Agents, Biomarkers, Tumor, Cell Death, Drug Design, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Genetic Therapy, Humans, Molecular Targeted Therapy, Neoplasms, Signal Transduction, Translational Medical Research