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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

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

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  • Medientyp: E-Artikel
  • Titel: Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells
  • Beteiligte: 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
  • Erschienen: eLife Sciences Publications, Ltd, 2019
  • Erschienen in: eLife, 8 (2019)
  • Sprache: Englisch
  • DOI: 10.7554/elife.43333
  • ISSN: 2050-084X
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: 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.
  • Zugangsstatus: Freier Zugang