Harnessing synthetic lethal interactions in anticancer drug discovery

Abstract

A primary goal of modern cancer drug development is the identification of targeted therapeutics that specifically kill tumour cells while leaving normal healthy cells unharmed. Synthetic lethality began as a description of genetic interactions that were observed in model organisms, but it is rapidly growing into a major strategy in the search for the next generation of targeted cancer therapies. Synthetic lethality is based on the genetic interaction between two genes. Inhibition of either gene alone has no effect on viability, but the combined inhibition of the two genes results in cell death. Cancer cells are frequently distinguished from normal cells by defects in specific genes that drive their growth and metastasis, and so the identification of genes or drugs that have a synthetic lethal interaction with cancer-promoting genes represents a compelling approach for the development of targeted therapies. The advent of RNA interference technologies allows whole-genome screening to uncover novel genetic interactions, whereas screening of small-molecule libraries can reveal novel lead agents for cancers with specific genetic mutations. Mutations in both gain-of-function oncogenes and loss-of-function tumour suppressor genes can be targeted. Conditional synthetic lethality exploits changes in gene expression that are induced by the tumour microenvironment, leading to an additional layer of specificity. DNA repair genes that are mutated in some cancers have been the most common targets of synthetic lethality studies so far, and these studies are the most clinically developed. Among the findings are the selective sensitivity of BRCA-deficient breast cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors and the importance of certain DNA polymerases for the survival of colorectal carcinomas that are defective in DNA mismatch repair proteins. PARP inhibitors have demonstrated clinical efficacy in BRCA-mutant breast and ovarian tumours. This Review explores how synthetic lethality screening can be used to identify new interactions and molecules for the treatment of cancer.