WRN helicase addiction in MSI-H colorectal cancer: biomarker-guided pharmacology, resistance evolution, and implications for other gastrointestinal cancers
- 1Department of Gastrointestinal Thyroid and Breastsurgery, Chongqing University Affiliated Qianjiang Hospital, Chongqing, China
Abstract
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.
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BibTeX
@article{zhang2026helicase,
title = {{WRN helicase addiction in MSI-H colorectal cancer: biomarker-guided pharmacology, resistance evolution, and implications for other gastrointestinal cancers}},
author = {Peng Zhang and Jiangsu Gan and Hongying Wang and Yali Xiong},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1962228},
url = {https://doi.org/10.3389/fphar.2026.1962228},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - WRN helicase addiction in MSI-H colorectal cancer: biomarker-guided pharmacology, resistance evolution, and implications for other gastrointestinal cancers
AU - Peng Zhang
AU - Jiangsu Gan
AU - Hongying Wang
AU - Yali Xiong
PY - 2026
DA - 2026/10/12
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1962228
UR - https://doi.org/10.3389/fphar.2026.1962228
AB - 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.
SN - 1663-9812
ER -