WRN helicase is a synthetic lethal target in microsatellite unstable cancers

Edmond M. Chan, Tsukasa Shibue, James M. McFarland, Benjamin Gaeta, Mahmoud Ghandi, Nancy Dumont, Alfredo Gonzalez, Justine S. McPartlan, Tianxia Li, Yanxi Zhang, Jie Liu, Jean-Bernard Lazaro, Peili Gu, Cortt G. Piett, Annie Apffel, Syed O. Ali, Rebecca Deasy, Paula Keskula, Raymond W. S. Ng, Emma A. Roberts, Elizaveta Reznichenko, Lisa Leung, Maria Alimova, Monica Schenone, Mirazul Islam, Yosef E. Maruvka, Yang Liu, Jatin Roper, Srivatsan Raghavan, Marios Giannakis, Yuen-Yi Tseng, Zachary D. Nagel, Alan D’Andrea, David E. Root, Jesse S. Boehm, Gad Getz, Sandy Chang, Todd R. Golub, Aviad Tsherniak, Francisca Vazquez () and Adam J. Bass ()
Additional contact information
Edmond M. Chan: Broad Institute of Harvard and MIT
Tsukasa Shibue: Broad Institute of Harvard and MIT
James M. McFarland: Broad Institute of Harvard and MIT
Benjamin Gaeta: Broad Institute of Harvard and MIT
Mahmoud Ghandi: Broad Institute of Harvard and MIT
Nancy Dumont: Broad Institute of Harvard and MIT
Alfredo Gonzalez: Broad Institute of Harvard and MIT
Justine S. McPartlan: Broad Institute of Harvard and MIT
Tianxia Li: Harvard Medical School
Yanxi Zhang: Harvard Medical School
Jie Liu: Harvard Medical School
Jean-Bernard Lazaro: Harvard Medical School
Peili Gu: Yale University School of Medicine
Cortt G. Piett: Harvard T. H. Chan School of Public Health
Annie Apffel: Broad Institute of Harvard and MIT
Syed O. Ali: Broad Institute of Harvard and MIT
Rebecca Deasy: Broad Institute of Harvard and MIT
Paula Keskula: Broad Institute of Harvard and MIT
Raymond W. S. Ng: Broad Institute of Harvard and MIT
Emma A. Roberts: Harvard Medical School
Elizaveta Reznichenko: Harvard Medical School
Lisa Leung: Broad Institute of Harvard and MIT
Maria Alimova: Broad Institute of Harvard and MIT
Monica Schenone: Broad Institute of Harvard and MIT
Mirazul Islam: Broad Institute of Harvard and MIT
Yosef E. Maruvka: Broad Institute of Harvard and MIT
Yang Liu: Broad Institute of Harvard and MIT
Jatin Roper: Duke University
Srivatsan Raghavan: Broad Institute of Harvard and MIT
Marios Giannakis: Broad Institute of Harvard and MIT
Yuen-Yi Tseng: Broad Institute of Harvard and MIT
Zachary D. Nagel: Broad Institute of Harvard and MIT
Alan D’Andrea: Harvard Medical School
David E. Root: Broad Institute of Harvard and MIT
Jesse S. Boehm: Broad Institute of Harvard and MIT
Gad Getz: Broad Institute of Harvard and MIT
Sandy Chang: Yale University School of Medicine
Todd R. Golub: Broad Institute of Harvard and MIT
Aviad Tsherniak: Broad Institute of Harvard and MIT
Francisca Vazquez: Broad Institute of Harvard and MIT
Adam J. Bass: Broad Institute of Harvard and MIT

Nature, 2019, vol. 568, issue 7753, 551-556

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (10)

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1102-x Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:568:y:2019:i:7753:d:10.1038_s41586-019-1102-x

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1102-x

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().