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Harnessing synthetic lethal interactions in anticancer drug discovery

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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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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Glossary

Small interfering RNA

(siRNA). A sequence of double-stranded RNA, generally 21 nucleotides in length, which targets specific mRNA sequences for degradation or inhibits translation of specific genes. Synthetic siRNAs can be introduced into a cell by transfection but they are short-lived.

Poly(ADP-ribose) polymerase

(PARP). A family of enzymes that catalyses the conversion of nicotinamide adenine dinucleotide into nicotinamide and polymers of ADP-ribose at glutamic acid residues of nuclear proteins. These enzymes are involved in a variety of cellular processes, notably DNA repair.

Short hairpin RNA

(shRNA). A plasmid or vector-based method for producing stable gene silencing. A promoter drives transcription of a target sequence, which forms a hairpin loop that is processed by the cellular RNA interference machinery, thereby forming small interfering RNAs to silence a particular gene.

Replication fork

The structure formed from the unwinding and breaking of the hydrogen bond of the two strands of DNA during replication. Each individual strand of DNA becomes a template for replication.

Knudson two-hit hypothesis

A model that proposes that cancer is a genetic disease and that successive genetic alterations in both alleles are needed to turn a normal cell into a cancer cell. In spontaneous cancers, two successive rare events must occur but in cases of hereditary susceptibility to cancer, inheritance of a damaged gene followed by a rare event results in mutation.

Clonogenic survival curve

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.

Autophagy

A catabolic process that sequesters and recycles cellular components, including organelles and long-lived proteins, in response to diverse stimuli. Autophagosomes form via invagination of the cell membrane, creating double-membrane vesicles. These autophagic vesicles then fuse with lysosomes, creating autophagolysosomes in which the contents of the cell are degraded by acidic lysosomal hydrolases.

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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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