Epigenetic synthetic lethality approaches in cancer therapy

Abstract

The onset and development of malignant tumors are closely related to epigenetic modifications, and this has become a research hotspot. In recent years, a variety of epigenetic regulators have been discovered, and corresponding small molecule inhibitors have been developed, but their efficacy in solid tumors is generally poor. With the introduction of the first synthetic lethal drug (the PARP inhibitor olaparib in ovarian cancer with BRCA1 mutation), research into synthetic lethality has also become a hotspot. High-throughput screening with CRISPR-Cas9 and shRNA technology has revealed a large number of synthetic lethal pairs involving epigenetic-related synthetic lethal genes, such as those encoding SWI/SNF complex subunits, PRC2 complex subunits, SETD2, KMT2C, and MLL fusion proteins. In this review, we focus on epigenetic-related synthetic lethal mechanisms, including synthetic lethality between epigenetic mutations and epigenetic inhibitors, epigenetic mutations and non-epigenetic inhibitors, and oncogene mutations and epigenetic inhibitors.

Keywords: Cancer; Epigenetic regulation; Mutation; SWI/SNF; Synthetic lethal.

Fig. 1

Epigenetic synthetic lethality approaches. a In normal cells, inhibiting one molecule in a synthetic lethal pair may lead to a compensatory response of another molecule, and therefore the cells survive. b Mutations in cancer cells are represented by red stars. In cancer cells with mutations, one molecule of synthetic lethal part has changed, and the specific inhibitor has inhibited another molecule, so it cannot produce complementarity or antagonism, leading to cell death. This review mainly introduces three epigenetic synthesis of lethal strategies. Strategy 1 uses epigenetic inhibitors in cells with epigenetic mutations cells; strategy 2 uses non-epigenetic inhibitors in cells with epigenetic mutations; and strategy 3 uses epigenetic inhibitors in cells with non-epigenetic mutations. Specific mutations and inhibitors are shown in the figure