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Elife. 2019 Mar 25;8. pii: e43333. doi: 10.7554/eLife.43333.

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

Author information

1
Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
2
Research Institute of Molecular Pathology, Vienna, Austria.
3
Division of Gastroenterology, Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, Ann Arbor, United States.
4
Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, United States.
#
Contributed equally

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.

KEYWORDS:

WRN; cancer biology; colorectal cancer; helicase; human; microsatellite instability; mismatch repair; targeted therapy

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