RT Journal Article
SR Electronic
T1 WRN Helicase is a Synthetic Lethal Target in Microsatellite Unstable Cancers
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 502070
DO 10.1101/502070
A1 Edmond M. Chan
A1 Tsukasa Shibue
A1 James McFarland
A1 Benjamin Gaeta
A1 Justine S. McPartlan
A1 Mahmoud Ghandi
A1 Jie Bin Liu
A1 Jean-Bernard Lazaro
A1 Nancy Dumont
A1 Alfredo Gonzalez
A1 Annie Apffel
A1 Syed O. Ali
A1 Lisa Leung
A1 Emma A. Roberts
A1 Elizaveta Reznichenko
A1 Mirazul Islam
A1 Maria Alimova
A1 Monica Schenone
A1 Yosef Maruvka
A1 Yang Liu
A1 Alan D’Andrea
A1 David E. Root
A1 Jesse S. Boehm
A1 Gad Getz
A1 Todd R. Golub
A1 Aviad Tsherniak
A1 Francisca Vazquez
A1 Adam J. Bass
YR 2018
UL http://biorxiv.org/content/early/2018/12/20/502070.abstract
AB Synthetic lethality, an interaction whereby the co-occurrence of two or more genetic events lead to cell death but one event alone does not, can be exploited to develop novel cancer therapeutics1. DNA repair processes represent attractive synthetic lethal targets since many cancers exhibit an impaired DNA repair pathway, which can lead these cells to become dependent on specific repair proteins2. The success of poly (ADP-ribose) polymerase 1 (PARP-1) inhibitors in homologous recombination-deficient cancers highlights the potential of this approach in clinical oncology3,4. Hypothesizing that other DNA repair defects would give rise to alternative synthetic lethal relationships, we asked if there are specific dependencies in cancers with microsatellite instability (MSI), which results from impaired DNA mismatch repair (MMR). Here we analyzed data from large-scale CRISPR/Cas9 knockout and RNA interference (RNAi) silencing screens and found that the RecQ DNA helicase WRN was selectively essential in MSI cell lines, yet dispensable in microsatellite stable (MSS) cell lines. WRN depletion induced double-strand DNA breaks and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models specifically required the helicase activity, but not the exonuclease activity of WRN. These findings expose WRN as a synthetic lethal vulnerability and promising drug target in MSI cancers.