WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers
Cancers with faulty DNA proof-reading depend on one particular unwinding enzyme to survive. Blocking it kills them and spares normal cells.
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.
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.
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