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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Survival
  • DNA Mismatch Repair
  • Humans
  • Microsatellite Instability*
  • Models, Theoretical
  • Neoplasms / therapy*
  • Werner Syndrome Helicase / antagonists & inhibitors*
  • Werner Syndrome Helicase / genetics

Substances

  • Werner Syndrome Helicase