{"entity":{"id":"wrn","kind":"target","name":"WRN helicase (MSI-high cancers)","aka":[],"tldr":"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.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Werner_syndrome_ATP-dependent_helicase","links":[{"label":"WRN dependency (Nature 2019)","url":"https://doi.org/10.1038/s41586-019-1102-x"}],"tags":["gap-fill"],"related":[],"cancers":["colorectal","endometrial","gastric"],"sections":[],"technologies":["synthetic-lethality-approaches","crispr-screens","cancer-cell-line-encyclopedias"],"targets":[],"drugs":["ndi-219216"],"companies":["novartis","roche-genentech","gsk"],"institutions":[],"pathways":[],"terms":["msi","synthetic-lethality","lynch-syndrome"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-chan-nature"],"journals":[],"dependsOn":[],"notes":[],"symbol":"WRN","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"few-types","specificityNote":"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.)","specificitySources":[{"label":"Human Protein Atlas WRN tissue","url":"https://www.proteinatlas.org/ENSG00000165392-WRN/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000165392 associations","url":"https://platform.opentargets.org/target/ENSG00000165392/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:12791","ensembl":"ENSG00000165392","uniprot":"Q14191","entrez":"7486","firstDescribed":1996,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Yu C.-E. et al, Science, 1996, \"Positional cloning of the Werner's syndrome gene\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/8602509/","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.","whereFound":["MSI-H colorectal cancer (~15% of CRC; dependency)","MSI-H endometrial cancer (~30%)","MSI-H gastric cancer (~20%)","Lynch syndrome tumours"],"targetClass":"enzyme","prevalence":[{"cancerId":"colorectal","pct":"15","measure":"MSI-H (WRN-dependent)"},{"cancerId":"endometrial","pct":"30","measure":"MSI-H"},{"cancerId":"gastric","pct":"20","measure":"MSI-H"}]},"route":"/targets/wrn/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"endometrial","kind":"cancer","name":"Endometrial cancer","route":"/cancers/endometrial/"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/"}],"technology":[{"id":"cancer-cell-line-encyclopedias","kind":"technology","name":"Cancer cell line encyclopedias and dependency maps","route":"/technologies/cancer-cell-line-encyclopedias/"},{"id":"crispr-screens","kind":"technology","name":"CRISPR functional genomics","route":"/technologies/crispr-screens/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"drug":[{"id":"eik1005","kind":"drug","name":"EIK1005","route":"/drugs/eik1005/"},{"id":"ndi-219216","kind":"drug","name":"NDI-219216","route":"/drugs/ndi-219216/"}],"company":[{"id":"gsk","kind":"company","name":"GSK","route":"/companies/gsk/"},{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"},{"id":"roche-genentech","kind":"company","name":"Roche / Genentech","route":"/companies/roche-genentech/"}],"term":[{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","route":"/terms/lynch-syndrome/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"}],"paper":[{"id":"paper-depmap-tsherniak-cell-2017","kind":"paper","name":"Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without","route":"/key-papers/paper-depmap-tsherniak-cell-2017/"},{"id":"paper-chan-nature","kind":"paper","name":"WRN helicase is a synthetic lethal target in microsatellite unstable cancers","route":"/key-papers/paper-chan-nature/"}],"pathway":[{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"},{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","route":"/pathways/synthetic-lethality-map/"}]}}