The Concept of Synthetic Lethality in the Context of Anticancer Therapy

Abstract

Many chemicals kill cancer cells but their toxicity to normal cells limits their usefulness as anticancer drugs. Epigenetic and genetic alterations within cancer cells, as well as changes in their microenvironment, might increase their requirement for a particular molecular target (or targets) relative to normal cells, creating an opportunity for selectivity. Two genes are synthetic lethal if mutation of either gene alone is compatible with viability but mutation of both leads to death. Inhibiting the products of genes that are synthetic lethal to cancer-causing mutations should, by definition, kill cells that harbour such mutations, while sparing normal cells. Most drugs induce a loss-of-function phenotype. High-throughput screens using matched cell-line pairs and chemical libraries allow the identification of chemicals that inhibit or kill cells in a genotype-specific manner. The challenge in this setting is to identify the relevant target (or targets) of compounds that score positively. Genome-wide RNA-interference screens can now be used to identify synthetic lethal interactions in cells that are derived from higher eukaryotes, including humans. Gene–gene interactions, including synthetic lethal interactions that are discovered in cell-culture experiments, will ultimately need to be validated in vivo. It seems likely that some gene–gene interactions will be highly robust, whereas others might be valid only in specific cells or under specific experimental conditions.