PT  - JOURNAL ARTICLE
AU  - Simone Lieb
AU  - Silvia Blaha-Ostermann
AU  - Elisabeth Kamper
AU  - Katharina Ehrenhöfer-Wölfer
AU  - Andreas Schlattl
AU  - Andreas Wernitznig
AU  - Jesse J. Lipp
AU  - Kota Nagasaka
AU  - Gerd Bader
AU  - Ralph A. Neumüller
AU  - Norbert Kraut
AU  - Mark A. Pearson
AU  - Mark Petronczki
AU  - Simon Wöhrle
TI  - Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells
AID  - 10.1101/530659
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 530659
4099  - http://biorxiv.org/content/early/2019/01/26/530659.short
4100  - http://biorxiv.org/content/early/2019/01/26/530659.full
AB  - Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent large-scale genomic profiling and functional screening of cancer cell lines we identified Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair is frequently detected in human malignancies, in particular in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in the emergence of chromosome breaks, chromatin bridges and micronuclei highlighting defective genome integrity. WRN variants harboring mutations abrogating the ATPase function of WRN helicase fail to rescue the viability phenotype of WRN-depleted MSI-H colorectal cells. Our study suggests that pharmacological inhibition of WRN helicase function might represent a novel opportunity to develop a targeted therapy for MSI-H cancers.