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

eLife

Janine Rippka¹  Mark A Pearson¹  Elisabeth Kamper¹  Silvia Blaha-Ostermann¹  Simone Lieb¹  Jesse J Lipp¹  Andreas Wernitznig¹  Mark Petronczki¹  Andreas Schlattl¹  Simon Wöhrle¹  Cornelia Schwarz¹  Katharina Ehrenhöfer-Wölfer¹  Ralph A Neumüller¹  Gerd Bader¹  Norbert Kraut¹  Ajay Goel²  Minoru Koi³  Petra van der Lelij⁴  Kota Nagasaka⁴  Jan-Michael Peters⁴ 

[1] Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria;Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, United States;Division of Gastroenterology, Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, Ann Arbor, United States;Research Institute of Molecular Pathology, Vienna, Austria;

关键词: WRN;    helicase;    mismatch repair;    microsatellite instability;    colorectal cancer;    targeted therapy;   

DOI  :  10.7554/eLife.43333

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown