Synthetic lethality: emerging targets and opportunities in melanoma

Abstract

Great progress has been made in the treatment of melanoma through use of targeted therapies and immunotherapy. One approach that has not been fully explored is synthetic lethality, which exploits somatically acquired changes, usually driver mutations, to specifically kill tumour cells. We outline the various approaches that may be applied to identify synthetic lethal interactions and define how these interactions may drive drug discovery efforts.

Keywords: CRISPR; melanoma genomics; preclinical models; synthetic lethality; therapeutic target.

Figure 1

The concept of using synthetic lethality as a therapeutic strategy in cancer. (A) Synthetic lethality: The loss of gene A or gene B in isolation is compatible with cellular viability, whereas loss of both genes together leads to cellular lethality. A normal cell therefore would be able to tolerate inhibition of gene A, whilst for a tumour cell that has already lost the function of gene B, inhibition of gene A is lethal. (B) Synthetic dose lethality: Overexpression or overactivation of gene B leads to cellular dependence on gene A. Whilst normal cells are able to tolerate inhibition of gene A, in tumour cells that overexpress gene B, inhibition of gene A is lethal. Key: regular circle – non‐malignant cell; irregular circle – tumour cell; red cells are those with a complement of mutations incompatible with viability; tablet – drug inhibition; cross – loss of gene function; thickened arrow – gene over‐expression; lightning bolt – gene mutation.