Harnessing Synthetic Lethal Interactions for Personalized Medicine

Abstract

Two genes are said to have synthetic lethal (SL) interactions if the simultaneous mutations in a cell lead to lethality, but each individual mutation does not. Targeting SL partners of mutated cancer genes can kill cancer cells but leave normal cells intact. The applicability of translating this concept into clinics has been demonstrated by three drugs that have been approved by the FDA to target PARP for tumors bearing mutations in BRCA1/2. This article reviews applications of the SL concept to translational cancer medicine over the past five years. Topics are (1) exploiting the SL concept for drug combinations to circumvent tumor resistance, (2) using synthetic lethality to identify prognostic and predictive biomarkers, (3) applying SL interactions to stratify patients for targeted and immunotherapy, and (4) discussions on challenges and future directions.

Keywords: biomarker; cancer; genetic interaction; precision medicine; synthetic lethal.

Figure 1

A graphic illustration of synthetic lethality. (a,c) Gene A and gene B are synthetic lethal when simultaneous mutation of gene A and B leads to cell death, but a single mutation of either does not. (b) The SL concept can be exploited to inhibit the SL partner (Gene A) of a mutant Gene B in a tumor cell.

Figure 2

A graphical display of the approach in [31,32,33] to discover prognostic biomarkers. Gene expression of cancerous versus non-cancerous tissues was used to select SL gene pairs relevant to a cancer under study, from the collected SL pairs. This procedure resulted in ~20 genes for immunohistochemistry (IHC). Then combinations of IHC and overall survival of patients were analyzed by Cox regression to yield prognostic markers, which were further validated by at least one external data set such as TCGA.