WRN helicase is a synthetic lethal target in microsatellite unstable cancers

• Published in: Nature (London) Vol. 568; no. 7753; pp. 551 - 556
• Main Authors: Chan, Edmond M., Shibue, Tsukasa, McFarland, James M., Gaeta, Benjamin, Ghandi, Mahmoud, Dumont, Nancy, Gonzalez, Alfredo, McPartlan, Justine S., Li, Tianxia, Zhang, Yanxi, Bin Liu, Jie, Lazaro, Jean-Bernard, Gu, Peili, Piett, Cortt G., Apffel, Annie, Ali, Syed O., Deasy, Rebecca, Keskula, Paula, Ng, Raymond W. S., Roberts, Emma A., Reznichenko, Elizaveta, Leung, Lisa, Alimova, Maria, Schenone, Monica, Islam, Mirazul, Maruvka, Yosef E., Liu, Yang, Roper, Jatin, Raghavan, Srivatsan, Giannakis, Marios, Tseng, Yuen-Yi, Nagel, Zachary D., D’Andrea, Alan, Root, David E., Boehm, Jesse S., Getz, Gad, Chang, Sandy, Golub, Todd R., Tsherniak, Aviad, Vazquez, Francisca, Bass, Adam J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2019; Nature Publishing Group
• Subjects: 13; 13/2; 13/89; 14; 14/1; 14/19; 14/35; 38/39; 38/91; 42/41; 631/67/1059/602; 631/67/68; 631/67/69; 96/1; Adenosine diphosphate; Analysis; Apoptosis; Apoptosis - genetics; Biomarkers; Cancer; Cell cycle; Cell Cycle Checkpoints - genetics; Cell death; Cell Line, Tumor; CRISPR; CRISPR-Cas Systems - genetics; CRISPR-Cas technology; Datasets; Deoxyribonucleic acid; Dependence; Depletion; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA helicase; DNA repair; Exonuclease; Gene expression; Genetic research; Genomes; Helicases; Homologous recombination; Homology; Humanities and Social Sciences; Humans; Instability; Kinases; Lethality; Letter; Microsatellite Instability; Microsatellite Repeats - genetics; Mismatch repair; Models, Genetic; multidisciplinary; Mutation; Neoplasms - genetics; Neoplasms - pathology; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; RecQ protein; Repair; Ribose; RNA Interference; RNA-mediated interference; Science; Science (multidisciplinary); Stability; Stability analysis; Synthetic biology; Synthetic Lethal Mutations - genetics; Tumor Suppressor Protein p53 - metabolism; Werner syndrome; Werner Syndrome Helicase - deficiency; Werner Syndrome Helicase - genetics; United States > US
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-019-1102-x

Synthetic lethality—an interaction between two genetic events through which the co-occurrence of these two genetic events leads to cell death, but each event alone does not—can be exploited for cancer therapeutics 1 . DNA repair processes represent attractive synthetic lethal targets, because many cancers exhibit an impairment of a DNA repair pathway, which can lead to dependence on specific repair proteins 2 . The success of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors in cancers with deficiencies in homologous recombination highlights the potential of this approach 3 . Hypothesizing that other DNA repair defects would give rise to synthetic lethal relationships, we queried dependencies in cancers with microsatellite instability (MSI), which results from deficient DNA mismatch repair. Here we analysed data from large-scale silencing screens using CRISPR–Cas9-mediated knockout and RNA interference, and found that the RecQ DNA helicase WRN was selectively essential in MSI models in vitro and in vivo, yet dispensable in models of cancers that are microsatellite stable. Depletion of WRN induced double-stranded DNA breaks and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models required the helicase activity of WRN, but not its exonuclease activity. These findings show that WRN is a synthetic lethal vulnerability and promising drug target for MSI cancers. Depletion of the DNA helicase WRN induced double-stranded DNA breaks, and promoted apoptosis and cell cycle arrest selectively in cancers with microsatellite instability, indicating that WRN is a promising drug target for the treatment of these cancers.