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On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells

de Gabriele Picco, Yanhua Rao, Angham Al Saedi, Samantha J. Walker, Shriram Bhosle, Yang Lee, Sara F. Vieira, Maria Garcia-Casado, Gilberto Valdes Garcia, Kieron May, Francesco Sassi, Inigo Barrio Hernandez, Mamta Sharma, Cansu Dincer, Theo Bell, Anastasia Kavasakali, Ray Shenje, Cuthbert Martyr, Edward Brnardic, Nanhua Deng, Hristina Grigorova Dimitrova, Emre Karakoc, Sandeep Sundara Rajan, Nicola Chan, Emma Hitch, Katrina McCarten, Camille Fourneaux, Zoe Hewitson, Howard Lightfoot, Syd Barthorpe, James P. Phelan, Phil Landis, Brian Jones, Diana Munoz, Jay Prakash, Paul Barsanti, Josh Taygerly, Michael P. DeMartino, Emanuel Gonçalves, Andrea Bertotti, Livio Trusolino, Mike White, Geeta Sharma, Matthew A. Coelho, Jonathan Houseley, Benjamin Schwartz e Mathew J. Garnett

Publicado: 27 de dezembro de 2025
Servidor: bioRxiv
DOI: 10.64898/2025.12.23.695783

Resumo

Werner helicase inhibitors (WRNi) are in clinical development for microsatellite-unstable (MSI) tumors with defective DNA mismatch repair. Here, we investigate how cancer cell evolution shapes response to WRN inhibition and informs potential resistance mechanisms. Genome-wide CRISPR screens combined with WRN knockout did not identify bypass mechanisms, underscoring WRN’s essential, non-redundant function in MSI cells. Pharmacogenomic screens identified modulators of WRNi sensitivity, including SMARCAL1 , which links it to WRN-MSI synthetic lethality. Semi-saturation mutagenesis of WRN and prolonged drug treatment identified on-target WRN mutations driving acquired resistance to multiple WRNi in vitro and in vivo, which was mitigated by combination with standard chemotherapies. Some resistance mutations conferred broad cross-resistance, whereas others preserved sensitivity to alternative clinical-grade WRNi with distinct mechanism of action. Our findings could inform clinical trial design by suggesting the feasibility of real-time tracking of emerging resistance and enabling early therapeutic adaptations.

Significance

We present the first exploration of how MSI cancer cells evolve under the selective pressure of WRN helicase inhibition, providing a framework for understanding adaptive responses to this newly identified synthetic-lethal dependency. This study identifies on-target WRN mutations as key drivers of resistance in MSI cancers, supporting the use of combination strategies with other standard-of-care treatments to prevent resistance. It highlights how mutation tracking can guide therapeutic switching to clinically available WRN inhibitors with distinct mechanisms of action, thereby refining clinical development and potentially improving biomarker-informed patient outcomes.

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Picco et al. present a framework for monitoring and designing treatment strategies to respond to WRN inhibitor resistance as it emerges, using screening and co-treatment approaches to dissect the distinct mechanisms of action underlying resistance. The comparison of resistance arising from genetic…

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Avaliações PREreview de On-target mutations confer resistance to WRN helicase inhibitors in Microsatellite Unstable Cancer Cells

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