Harnessing synthetic lethal interactions in anticancer drug discovery

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.

Figure 1. Synthetic lethality

a | Organismal view. In model organisms, synthetic lethality describes the genetic interaction between two genes. If either gene is mutated by itself, the organism remains viable. The combination of a mutation in both genes is incompatible with viability and results in lethality. b | Pathway view. Two genes are considered to be synthetic lethal when they contribute to an essential process. For example, when either gene ‘A’, ‘B’ or ‘C’, or gene ‘1’, ‘2’ or ‘3’ is mutated, the organism or cell remains viable. However, the combination of these mutations (‘A’, ‘B’ or ‘C’ with ‘1’, ‘2’ or ‘3’) results in death.

Figure 2. Mammalian synthetic lethality screens for anticancer efficacy

a | Synthetic lethal screens can be used to identify genes or small-molecule compounds to specifically target tumour cells while sparing the normal tissue. A mutation in the first gene is essential to the development of cancer (for example, a loss-of-function mutation in a tumour suppressor gene or a gain-of-function mutation in an oncogene). The second gene would be identified either through an RNA interference (RNAi) library or it would directly be inhibited by a small-molecule compound. Inhibition of this second gene through RNAi or a small molecule alone would not interfere with tumour growth. Nonetheless, inhibiting the second gene in a tumour of a given genotype would result in selective cytotoxicity of the tumour. b | Isogenic cells that differ by only one essential cancer gene could be fluorescently tagged and mixed together in equal numbers. The cells would then be added to a 96-well plate and treated with a compound library. Fluorescence would be read over several days. Some compounds would not be toxic to either cell type; some would be selectively toxic to normal cells or selectively toxic to tumour cells; and some would be toxic to both genotypes. Validation of individual compounds through short-term and long-term survival assays — such as metabolic measurements or clonogenics — would then determine potential hits.

Figure 3. Example of a conditional synthetic lethality opportunity

Dichloroacetate (DCA) inhibits the function of pyruvate dehydrogenase kinase (PDK) in mitochondria, relieving the inhibition of pyruvate dehydrogenase (PD H). P DH catalyses the conversion of pyruvate to acetyl CoA, which is an important substrate of the citric acid cycle. When PDH is active, the citric acid cycle utilizes oxygen, increasing oxygen consumption and consequently resulting in hypoxia. The hypoxic condition can then be targeted by synthetic lethality.