Loading
Life sciences · Journal article
Frontiers in Pharmacology · October 12, 2026
No summary has been generated for this record yet. What follows is drawn from its source metadata only.
Journal article.
No findings were extractable from the material analysed.
Safety was not reported in the material analysed. Check the source before drawing any conclusion about harm.
The source did not state who this applies to in practice.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
This record has not been graded across any dimension yet. Treat the label above as provisional and read the source.
What is missing. This record has no bottom line, key findings, reported figures, evidence dimensions. That is a gap in the analysis, not a judgement about the study.
Microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) cancers are enriched for dependence on Werner syndrome RecQ helicase (WRN), a synthetic-lethal vulnerability mechanistically linked to expanded TA-dinucleotide repeats, non-B DNA structures, and replication-associated genome instability. However, WRN dependence is not universal among dMMR/MSI-H tumors, indicating that MSI status is an enrichment biomarker rather than a complete predictor of biological dependency. In this review, we synthesize recent advances in WRN structural and molecular pharmacology, with particular emphasis on colorectal cancer, where the strongest functional and pharmacological evidence currently exists. We distinguish four translational biomarker layers: pretreatment predictors of WRN dependency, target-engagement and DNA-damage pharmacodynamic markers, early treatment-response biomarkers, and acquired-resistance markers. We further examine reversible and covalent WRN inhibitors, mechanisms of primary and therapy-emergent resistance, immune and replication-stress-based combinations, and the expanding early-phase clinical landscape. Rather than proposing quantitative WRN dependency as a new biological concept, we present an evidence-graded pharmacological framework that links established substrate biology with drug exposure, target engagement, downstream DNA damage, treatment response, and resistance evolution. This framework may guide prospective biomarker development in MSI-H/dMMR colorectal cancer while identifying the evidence still required for broader application across other gastrointestinal malignancies.