WRN helicase is a synthetic lethal target in microsatellite unstable cancers

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 c...

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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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally: Edmond M. Chan and Tsukasa Shibue E.M.C., T.S., F.V., and A.J.B. initiated the project, designed, and supervised the research plan. J.M.M., M.Gh., Y.L., and Y.E.M. performed computational analysis of the CCLE and cancer dependency datasets under the supervision of D.E.R, J.S.B., G.G., T.R.G., A.T., F.V., and A.J.B.. E.M.C., T.S., B.G., and J.S.M. performed the viability experiments to validate the cancer dependency dataset findings with help from M.S., A.A., S.A.O., and L.L.. The rescue experiments with WRN overexpression were performed by E.M.C. and B.G.. The HCT116 viability experiments were performed by T.S. and B.G.. N.D., A.G., T.L., and Y.Z. performed in vivo experiments. The patient derived organoids were established by J.S.B., Y.Y.T., M.Gi., R.D., and P.K.. Organoid experiments were conducted by E.M.C. and T.S. with help from S.R., R.W.S.N, and J.R.. RNA extraction for mRNA-seq was performed by T.S. and analyzed by J.M.M. and M.I.. J.S.M. and T.S. performed and analyzed the cell cycle and apoptosis assays. Immunoblots were performed by T.S., E.M.C., B.G., and J.S.M. Immunofluorescence were performed by T.S., E.M.C., J.B.L., J.L., E.A.R, and E.R. and analyzed by T.S., E.M.C., J.B.L., J.L., M.A., and A.D.A.. S.C. and P.G. performed the telomere PNA-FISH experiment. Z.N. and C.G.P. performed the fluorescence-based flow-cytometric host cell reactivation assay. E.M.C., T.S., J.M.M., F.V., and A.J.B. wrote the manuscript. All the authors edited and approved the manuscript. Author Contributions
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-019-1102-x