Abstract LB-048: WRN helicase is a synthetic lethal target in microsatellite unstable cancers

Abstract

Abstract Microsatellite instability (MSI), a class of genetic hypermutability that arises from impaired DNA mismatch repair (MMR), contributes to the development of many malignancies including colon, endometrial, gastric, and ovarian cancers. While immune checkpoint blockade (ICB) has been an effective therapy for many patients with MSI cancers, numerous patients with MSI malignancies do not respond to ICB or the use of these agents are limited by their toxicity. Hence, there is still a pressing need to develop further therapies against MSI cancers. One approach to develop novel therapeutics is to leverage synthetic lethality, a phenomenon whereby the simultaneous occurrence of two or more genetic events lead to cell death but one event alone does not. DNA repair processes represent attractive synthetic lethal targets since many cancers exhibit an impaired DNA repair pathway, which can lead these cancers to become dependent on specific repair proteins. The success of poly (ADP ribose) polymerase (PARP) inhibitors in homologous recombination-deficient cancers highlights the potential of this approach. Hypothesizing that other DNA repair defects would give rise to alternative synthetic lethal relationships, we asked if there are specific dependencies in MSI cancers. Here, we analyzed data from large-scale CRISPR/Cas9 and RNA interference (RNAi) functional genomic screens and found that the RecQ DNA helicase WRN was selectively essential in MSI models in vitro and in vivo, but dispensable in microsatellite stable models. WRN silencing induced double-strand DNA breaks, activated a DNA-damage response, and promoted apoptosis and cell cycle arrest preferentially in MSI models. MSI cancer models specifically required WRN’s helicase activity, but not its exonuclease activity. These findings expose WRN as a synthetic lethal vulnerability and promising drug target for MSI cancers. Citation Format: Edmond M. Chan, Tsukasa Shibue, James McFarland, Benjamin Gaeta, Francisca Vazquez, Adam J. Bass. WRN helicase is a synthetic lethal target in microsatellite unstable cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-048.