{"entity":{"id":"idea-bio1-wrn-msi-programme","kind":"idea","name":"WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers","aka":[],"tldr":"Cancers with faulty DNA proof-reading depend on one particular unwinding enzyme to survive. Blocking it kills them and spares normal cells.","summary":"Microsatellite-unstable cancers accumulate expanded TA repeats that form secondary structures requiring WRN helicase to resolve; WRN loss is selectively lethal in MSI-high lines, one of the strongest synthetic-lethal signals from CRISPR screens. WRN inhibitors and degraders have entered early clinical trials. The strategic proposal is to test WRN inhibition specifically in MSI-high tumours that have failed immunotherapy, a group with no good options.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017)","url":"https://doi.org/10.1038/nrc.2017.36"}],"tags":[],"related":[],"cancers":["colorectal","endometrial"],"sections":[],"technologies":["synthetic-lethality-approaches","crispr-screens"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["msi","synthetic-lethality","tumour-agnostic"],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-resistance"],"keyPapers":["paper-dang-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"WRN inhibition produces objective responses in MSI-high tumours that have progressed on checkpoint blockade, at a rate materially higher than that of available chemotherapy.","rationale":"The dependency is genotype-defined, near-binary and reproducible across laboratories, which is rare; MSI status is already tested routinely, so patient selection needs no new diagnostic.","test":"Tumour-agnostic phase 2 in MSI-high, immunotherapy-refractory cancers with a pre-specified response threshold and paired biopsies for target engagement.","maturity":"early-clinical","actor":"industry","cost":"medium","horizonYears":4},"route":"/ideas/idea-bio1-wrn-msi-programme/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"endometrial","kind":"cancer","name":"Endometrial cancer","route":"/cancers/endometrial/"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/"},{"id":"endometrial-mmr-deficient","kind":"cancer","name":"Mismatch-repair-deficient endometrial cancer","route":"/cancers/endometrial-mmr-deficient/"}],"technology":[{"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/"}],"term":[{"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/"},{"id":"tumour-agnostic","kind":"term","name":"Tumour-agnostic (tissue-agnostic) approval","route":"/terms/tumour-agnostic/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-dang-nat-rev-cancer","kind":"paper","name":"Drugging the 'undruggable' cancer targets","route":"/key-papers/paper-dang-nat-rev-cancer/"}]}}