TY - JOUR TI - Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells AU - Lieb, Simone AU - Blaha-Ostermann, Silvia AU - Kamper, Elisabeth AU - Rippka, Janine AU - Schwarz, Cornelia AU - Ehrenhöfer-Wölfer, Katharina AU - Schlattl, Andreas AU - Wernitznig, Andreas AU - Lipp, Jesse J AU - Nagasaka, Kota AU - van der Lelij, Petra AU - Bader, Gerd AU - Koi, Minoru AU - Goel, Ajay AU - Neumüller, Ralph A AU - Peters, Jan-Michael AU - Kraut, Norbert AU - Pearson, Mark A AU - Petronczki, Mark AU - Wöhrle, Simon A2 - Heyer, Wolf-Dietrich A2 - Settleman, Jeffrey A2 - Heyer, Wolf-Dietrich A2 - Monnat, Ray A2 - Cejka, Petr VL - 8 PY - 2019 DA - 2019/03/25 SP - e43333 C1 - eLife 2019;8:e43333 DO - 10.7554/eLife.43333 UR - https://doi.org/10.7554/eLife.43333 AB - 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. KW - WRN KW - helicase KW - mismatch repair KW - microsatellite instability KW - colorectal cancer KW - targeted therapy JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -