Synthetic lethal vulnerabilities of cancer

Annu Rev Pharmacol Toxicol. 2015;55:513-31. doi: 10.1146/annurev-pharmtox-010814-124511. Epub 2014 Oct 9.

Abstract

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.

Keywords: clinical translation; drugs; genetic screens; synthetic lethality.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Cell Death / drug effects
  • Drug Design*
  • Epigenesis, Genetic / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Regulatory Networks / drug effects
  • Genetic Therapy / methods*
  • Humans
  • Molecular Targeted Therapy / methods*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Signal Transduction / drug effects
  • Translational Medical Research

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor