Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Chan, EM, Shibue, T, McFarland, JM, Gaeta, B, Ghandi, M, Dumont, N, Gonzalez, A, McPartlan, JS, Li, T, Zhang, Y, Bin Liu, J, Lazaro, J-B, Gu, P, Piett, CG, Apffel, A, Ali, SO, Deasy, R, Keskula, P, Ng, RWS, Roberts, EA, Reznichenko, E, Leung, L, Alimova, M, Schenone, M, Islam, M, Maruvka, YE, Liu, Y, Roper, J, Raghavan, S, Giannakis, M, Tseng, Y-Y, Nagel, ZD, D'Andrea, A, Root, DE, Boehm, JS, Getz, G, Chang, S, Golub, TR, Tsherniak, A, Vazquez, F, Bass, AJ |
Journal | Nature |
Volume | 568 |
Issue | 7753 |
Pages | 551-556 |
Date Published | 2019 04 |
ISSN | 1476-4687 |
Keywords | Apoptosis, Cell Cycle Checkpoints, Cell Line, Tumor, CRISPR-Cas Systems, DNA Breaks, Double-Stranded, Humans, Microsatellite Instability, Microsatellite Repeats, Models, Genetic, Neoplasms, RNA Interference, Synthetic Lethal Mutations, Tumor Suppressor Protein p53, Werner Syndrome Helicase |
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 therapeutics. 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. The success of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors in cancers with deficiencies in homologous recombination highlights the potential of this approach. 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. |
DOI | 10.1038/s41586-019-1102-x |
Pubmed | |
Alternate Journal | Nature |
PubMed ID | 30971823 |
PubMed Central ID | PMC6580861 |
Grant List | K08 CA198002 / CA / NCI NIH HHS / United States P30 DK034854 / DK / NIDDK NIH HHS / United States T32 CA009172 / CA / NCI NIH HHS / United States |
Nature DOI:10.1038/s41586-019-1102-x
WRN helicase is a synthetic lethal target in microsatellite unstable cancers.
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