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.
Development of Synthetic Lethality Anticancer Therapeutics
Published 2014 in Journal of Medicinal Chemistry
ABSTRACT
PUBLICATION RECORD
- Publication year
2014
- Venue
Journal of Medicinal Chemistry
- Publication date
2014-06-03
- Fields of study
Biology, Medicine, Chemistry
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- cell context dependence
The dependence of synthetic-lethality effects on the specific cellular and genetic background of a tumor.
- checkpoint inhibitors for p53 mutant cancers
Immune checkpoint-blocking agents discussed as a synthetic-lethality approach for cancers carrying p53 mutations.
Aliases: checkpoint inhibitors
- mechanisms underlying synthetic lethality
The biological interactions and pathways that create lethal effects when particular gene defects are combined.
Aliases: synthetic lethality mechanisms
- poly adp-ribose polymerase inhibitors for brca1- and brca2-mutant cancers
PARP-targeting drugs discussed as a synthetic-lethality strategy in tumors with BRCA1 or BRCA2 mutations.
Aliases: PARP inhibitors for BRCA1- and BRCA2-mutant cancers, PARP inhibitors
- small molecule agents targeting ras gene mutant cancers
Small-molecule compounds discussed as synthetic-lethality agents for cancers with RAS gene mutations.
Aliases: RAS-targeting small molecules, RAS mutant cancer agents
- synthetic lethality
A gene-pair interaction in which combining two otherwise tolerable defects produces cell death, forming the basis for selective cancer targeting.
- treatment response biomarkers
Biological markers proposed to help identify or predict which tumors will respond to synthetic-lethality therapy.
Aliases: response biomarkers
REFERENCES
CITED BY
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