# WRN helicase (MSI-high cancers)

Source: https://onco.cc/targets/wrn/  
OnCo record `wrn` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A DNA-unwinding enzyme that mismatch-repair-deficient cancers cannot live without; the first WRN inhibitors are in trials as a chemotherapy-free option for MSI-high tumours that fail immunotherapy.

## Summary

CRISPR screens (2019) identified WRN as a synthetic-lethal dependency in microsatellite-unstable (MSI-H/dMMR) cancers because expanded TA-dinucleotide repeats form secondary structures that only WRN helicase can resolve. First-in-class covalent WRN inhibitors (HRO761, RO7589831/VVD-133214, GSK4418959) entered phase 1 in 2023-24 with early responses in MSI-H colorectal cancer, including after checkpoint inhibitors. Relevant to ~15% of colorectal, ~30% of endometrial and ~20% of gastric cancers, and Lynch syndrome.

## Fields

- Kind: Target
- Last checked: 2026-09-08
- Tags: gap-fill
- Symbol: WRN
- Class: enzyme
- Biology: RecQ family 3'→5' DNA helicase and exonuclease; germline loss causes Werner progeroid syndrome; in MSI cancers its helicase (not exonuclease) activity prevents replication fork collapse at expanded (TA)n repeats.
- Where found: MSI-H colorectal cancer (~15% of CRC; dependency); MSI-H endometrial cancer (~30%); MSI-H gastric cancer (~20%); Lynch syndrome tumours

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Werner_syndrome_ATP-dependent_helicase
- WRN dependency (Nature 2019): https://doi.org/10.1038/s41586-019-1102-x

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Endometrial cancer](https://onco.cc/cancers/endometrial/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [Mismatch-repair deficient (MSI-high) colorectal cancer](https://onco.cc/cancers/msi-high-colorectal/)
- technologies: [Cancer cell line encyclopedias and dependency maps](https://onco.cc/technologies/cancer-cell-line-encyclopedias/), [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- drugs: [EIK1005](https://onco.cc/drugs/eik1005/), [NDI-219216](https://onco.cc/drugs/ndi-219216/)
- companies: [GSK](https://onco.cc/companies/gsk/), [Novartis](https://onco.cc/companies/novartis/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- terms: [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- key papers: [Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without](https://onco.cc/key-papers/paper-depmap-tsherniak-cell-2017/), [WRN helicase is a synthetic lethal target in microsatellite unstable cancers](https://onco.cc/key-papers/paper-chan-nature/)
- pathways: [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/)

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JSON: https://onco.cc/api/v1/entities/wrn.json