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Nature. 2019 Apr 10. doi: 10.1038/s41586-019-1102-x. [Epub ahead of print]

WRN helicase is a synthetic lethal target in microsatellite unstable cancers.

Author information

1
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
3
Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
4
Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA.
5
Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
6
Massachusetts General Hospital Cancer Center, Boston, MA, USA.
7
Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC, USA.
8
Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
9
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA.
10
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
11
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
12
Broad Institute of Harvard and MIT, Cambridge, MA, USA. vazquez@broadinstitute.org.
13
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. vazquez@broadinstitute.org.
14
Broad Institute of Harvard and MIT, Cambridge, MA, USA. adam_bass@dfci.harvard.edu.
15
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. adam_bass@dfci.harvard.edu.

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.

PMID:
30971823
DOI:
10.1038/s41586-019-1102-x

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