Anticipating on-target resistance to WRN inhibitors in microsatellite unstable cancers

Authors

Orcholski, M. E., Laterreur, N., Masud, W., Shenoy, S., Chapdelaine-Trepanier, V., Bowlan, J., Minju-OP, A., Cabre-Romans, J.-J., Sack, T., Fiore, C., Young, J. T., Alvarez-Quilon, A., Cuella-Martin, R.

Abstract

Leveraging WRN helicase dependency in microsatellite instability (MSI) cancers offers a synthetic lethal (SL) therapeutic opportunity, with several WRN inhibitors in development. However, the hypermutator nature of MSI tumors creates strong evolutionary pressure for rapid resistance. Here, we apply a multimodal functional genomics framework integrating base editing screens and deep mutational scanning to map on-target resistance to two clinical WRN inhibitors, HRO761 and VVD-214. We identify discrete resistance hotspots within WRN and demonstrate that single-allele (heterozygous) mutations at the drug-binding site are sufficient to abrogate WRN inhibitor-induced cytotoxicity. Resistance profiles diverged between HRO761 and VVD-214, revealing mutations that impair one but preserve sensitivity to the other. Genome-wide CRISPR screens further identified non-homologous end joining (NHEJ) factors and the checkpoint phosphatase WIP1 as tractable synthetic vulnerabilities that potentiate WRN inhibition. Together, these findings establish a framework for resistance-aware deployment of WRN inhibitors through rational drug selection, therapeutic switching, and combination strategies.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 26 Jan 2026.

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