Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells

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...

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Published in:eLife 2019-03, Vol.8
Main Authors: Lieb, Simone, Blaha-Ostermann, Silvia, Kamper, Elisabeth, Rippka, Janine, Schwarz, Cornelia, Ehrenhöfer-Wölfer, Katharina, Schlattl, Andreas, Wernitznig, Andreas, Lipp, Jesse J, Nagasaka, Kota, van der Lelij, Petra, Bader, Gerd, Koi, Minoru, Goel, Ajay, Neumüller, Ralph A, Peters, Jan-Michael, Kraut, Norbert, Pearson, Mark A, Petronczki, Mark, Wöhrle, Simon
Format: Article
Language:English
Subjects:
Cancer
Cancer Biology
Cell Line, Tumor
Cell Survival
Chromosomes
Colorectal cancer
Defects
Deoxyribonucleic acid
DNA
DNA helicase
DNA Mismatch Repair
DNA repair
Drinking water
Endometrial cancer
Endometrium
Genes
Genomes
helicase
Humans
Microsatellite Instability
Mismatch repair
Models, Theoretical
Mutation
Neoplasms - therapy
Phenotypes
Software
targeted therapy
Tumor cell lines
Tumor cells
Tumors
Werner Syndrome Helicase - antagonists & inhibitors
Werner Syndrome Helicase - genetics
Werner's syndrome
WRN
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.43333