title: Development of synthetic lethality anticancer therapeutics.
abstract: The concept of synthetic lethality (the creation of a lethal phenotype from the combined effects of mutations in two or more genes) has recently been exploited in various efforts to develop new genotype-selective anticancer therapeutics. These efforts include screening for novel anticancer agents, identifying novel therapeutic targets, characterizing mechanisms of resistance to targeted therapy, and improving efficacies through the rational design of combination therapy. This review discusses recent developments in synthetic lethality anticancer therapeutics, including poly ADP-ribose polymerase inhibitors for BRCA1- and BRCA2-mutant cancers, checkpoint inhibitors for p53 mutant cancers, and small molecule agents targeting RAS gene mutant cancers. Because cancers are caused by mutations in multiple genes and abnormalities in multiple signaling pathways, synthetic lethality for a specific tumor suppressor gene or oncogene is likely cell context-dependent. Delineation of the mechanisms underlying synthetic lethality and identification of treatment response biomarkers will be critical for the success of synthetic lethality anticancer therapy.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Unit 1489, The University of Texas MD Anderson Cancer Center , 1515 Holcombe Boulevard, Houston, Texas 77030, United States.
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D055808:Drug Discovery; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D018631:ras Proteins