1. WRN helicase is a synthetic lethal target in microsatellite unstable cancers
- Author
-
Gad Getz, James M. McFarland, Aviad Tsherniak, Francisca Vazquez, Benjamin Gaeta, Yosef E. Maruvka, Marios Giannakis, Mirazul Islam, Monica Schenone, Edmond M. Chan, Annie Apffel, Sandy Chang, Paula Keskula, Alfredo Gonzalez, Jesse S. Boehm, Maria Alimova, Justine S. McPartlan, Tsukasa Shibue, Srivatsan Raghavan, Jean-Bernard Lazaro, Peili Gu, Yang Liu, Yanxi Zhang, Elizaveta Reznichenko, Lisa Leung, Jatin Roper, Tianxia Li, David E. Root, Raymond W.S. Ng, Emma A. Roberts, Alan D. D'Andrea, Jie Bin Liu, Syed O. Ali, Todd R. Golub, Zachary D. Nagel, Mahmoud Ghandi, Cortt G. Piett, Adam J. Bass, Nancy Dumont, Yuen-Yi Tseng, and Rebecca Deasy
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Werner Syndrome Helicase ,DNA repair ,Apoptosis ,Article ,03 medical and health sciences ,0302 clinical medicine ,RNA interference ,Cell Line, Tumor ,Neoplasms ,medicine ,Humans ,Gene silencing ,DNA Breaks, Double-Stranded ,Polymerase ,Multidisciplinary ,Models, Genetic ,biology ,nutritional and metabolic diseases ,Helicase ,Microsatellite instability ,Cell Cycle Checkpoints ,medicine.disease ,3. Good health ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Microsatellite Instability ,RNA Interference ,DNA mismatch repair ,CRISPR-Cas Systems ,Tumor Suppressor Protein p53 ,Synthetic Lethal Mutations ,Homologous recombination ,Microsatellite Repeats - Abstract
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 therapeutics1. 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 proteins2. The success of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors in cancers with deficiencies in homologous recombination highlights the potential of this approach3. 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.
- Published
- 2019
- Full Text
- View/download PDF