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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.
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.
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.
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.
2 products aim at WRN helicase (MSI-high cancers): small molecules. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
Broadly expressed or essential: HPA finds the RNA at low tissue specificity; the 1 medicine aimed at it (NDI-219216) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA WRN: RNA low tissue specificity; no normal tissue stained high. Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Colorectal cancer, Endometrial cancer, Gastric & gastro-oesophageal junction cancer); Open Targets associates it with 0 specific cancer types at or above 0.5. (Rule 7 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas WRN tissue; Open Targets ENSG00000165392 associations
First described 1996. Earliest sequence paper UniProt cites for the protein: Yu C.-E. et al, Science, 1996, "Positional cloning of the Werner's syndrome gene". Source.
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.
RNA: low tissue specificity, detected in all normal tissues.
No normal tissue stained high; medium in Adrenal gland, Bronchus, Cerebellum, Cerebral cortex, Colon, Esophagus and more.
No cancer stained high; medium in carcinoid, cervical cancer, colorectal cancer, endometrial cancer.
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| 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.
EIK1005 is a small-molecule inhibitor from Eikon Therapeutics, in registered phase 2 trials for colorectal cancer, endometrial cancer.
NDI-219216 is an experimental small-molecule drug from Nimbus Wadjet in phase 2 trials, aimed at WRN helicase (MSI-high cancers).
One target page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
DepMap is the lookup table drug hunters use to ask: which cancers would die if we blocked this gene, and how would we recognise them? It generated targets such as WRN and PRMT5-MTAP now in clinical trials, and it is public.
Query 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.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics, Mismatch-repair deficient (MSI-high) colorectal cancer.
Shares EIK1005, Mismatch-repair deficient (MSI-high) colorectal cancer, Endometrial cancer, Colorectal cancer.
Shares Cancer cell line encyclopedias and dependency maps, Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without, Synthetic lethality, Synthetic lethality: paired dependencies.
Shares GSK, Mismatch-repair deficient (MSI-high) colorectal cancer, Endometrial cancer, Colorectal cancer.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics.
Shares Lynch syndrome, Mismatch repair & microsatellite instability, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Colorectal cancer.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics.