WRN helicase (MSI-high cancers)
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.
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.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · 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.
- 1 · What it is
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.
- 2 · What goes wrong in cancer
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.
- 3 · How drugs use it
No product in this corpus aims at WRN helicase (MSI-high cancers) yet. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
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.
- MSI-H colorectal cancer (~15% of CRC; dependency)
- MSI-H endometrial cancer (~30%)
- MSI-H gastric cancer (~20%)
- Lynch syndrome tumours
How common it is, by cancer
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Endometrial cancer | 30% | MSI-H | ||
| Gastric & gastro-oesophageal junction cancer | 20% | MSI-H | ||
| Colorectal cancer | 15% | MSI-H (WRN-dependent) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Latest papers
topQuery for this target: (TITLE:"WRN helicase" OR ABSTRACT:"WRN helicase" OR TITLE:"MSI-high cancers" OR ABSTRACT:"MSI-high cancers" OR TITLE:"WRN" OR ABSTRACT:"WRN") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about WRN helicase (MSI-high cancers), not a curated reading list.
Pages like this
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