Abstract |
Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent functional screening data of cancer cell lines we identify Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair (MMR), occurs frequently 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 severe genome integrity defects. ATP-binding deficient variants of WRN fail to rescue the viability phenotype of WRN-depleted MSI-H cancer cells. Reconstitution and depletion studies indicate that WRN dependence is not attributable to acute loss of MMR gene function but might arise during sustained MMR-deficiency. Our study suggests that pharmacological inhibition of WRN helicase function represents an opportunity to develop a novel targeted therapy for MSI-H cancers.
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Authors | Simone Lieb, Silvia Blaha-Ostermann, Elisabeth Kamper, Janine Rippka, Cornelia Schwarz, Katharina Ehrenhöfer-Wölfer, Andreas Schlattl, Andreas Wernitznig, Jesse J Lipp, Kota Nagasaka, Petra van der Lelij, Gerd Bader, Minoru Koi, Ajay Goel, Ralph A Neumüller, Jan-Michael Peters, Norbert Kraut, Mark A Pearson, Mark Petronczki, Simon Wöhrle |
Journal | eLife
(Elife)
Vol. 8
(03 25 2019)
ISSN: 2050-084X [Electronic] England |
PMID | 30910006
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2019, Lieb et al. |
Chemical References |
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Topics |
- Cell Line, Tumor
- Cell Survival
- DNA Mismatch Repair
- Humans
- Microsatellite Instability
- Models, Theoretical
- Neoplasms
(therapy)
- Werner Syndrome Helicase
(antagonists & inhibitors, genetics)
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