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  • Review Article
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Harnessing synthetic lethal interactions in anticancer drug discovery

Nature Reviews Drug Discovery volume 10, pages 351–364 (2011)Cite this article

Subjects

Key Points

  • 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.

Abstract

Unique features of tumours that can be exploited by targeted therapies are a key focus of current cancer research. One such approach is known as synthetic lethality screening, which involves searching for genetic interactions of two mutations whereby the presence of either mutation alone has no effect on cell viability but the combination of the two mutations results in cell death. The presence of one of these mutations in cancer cells but not in normal cells can therefore create opportunities to selectively kill cancer cells by mimicking the effect of the second genetic mutation with targeted therapy. Here, we summarize strategies that can be used to identify synthetic lethal interactions for anticancer drug discovery, describe examples of such interactions that are currently being investigated in preclinical and clinical studies of targeted anticancer therapies, and discuss the challenges of realizing the full potential of such therapies.

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Figure 1: Synthetic lethality.
Figure 2: Mammalian synthetic lethality screens for anticancer efficacy.
Figure 3: Example of a conditional synthetic lethality opportunity.

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Acknowledgements

This work was supported by the following grants from the US National Cancer Institute: NCI-CA-67166 (A.J.G), NCI-CA-88480 (A.J.G) and NCI-CA-123823 (D.A.C). It was also supported by a grant from Action to Cure Kidney Cancer (A.J.G.). We apologize to colleagues whose work we failed to cite.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of California, San Francisco, 94143-1331, California, USA

    Denise A. Chan

  2. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, 94305-5152, California, USA

    Amato J. Giaccia

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Correspondence to Amato J. Giaccia.

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Amato J. Giaccia is a founder of Ruga Corporation. Denise A. Chan is a scientific consultant for Ruga Corporation.

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The standard method for determining the effectiveness of a particular treatment on the proliferation of cells. Cells are plated in a tissue culture dish and allowed to attach overnight. The plates are then treated and grown until single cells form colonies, which are then fixed, stained and counted.

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Chan, D., Giaccia, A. Harnessing synthetic lethal interactions in anticancer drug discovery. Nat Rev Drug Discov 10, 351–364 (2011). https://doi.org/10.1038/nrd3374

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