Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC). The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of immunotherapy patients are refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic-lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR CRC preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency.These data show the potential of therapeutically targeting WRN in dMMR/MSI-H CRC patients, and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies. SIGNIFICANCEWe found that a large, diverse set of dMMR/MSI-H CRC preclinical models, including models of treatment refractory disease, are WRN dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H CRC tumors as a monotherapy or in combination with targeted agents, chemotherapy or immunotherapy. INTRODUCTIONDNA mismatch repair (MMR) is an evolutionarily conserved process that recognizes and repairs spontaneously mis-incorporated bases during DNA replication. Microsatellite instability (MSI) is caused by impaired MMR and is a ubiquitous feature in cancer, observed in >20 different tumor types and frequently present in colon, ovarian, endometrial, and gastric cancer, with hundreds of thousands of MSI cancer diagnoses worldwide each year.Lynch syndrome is caused by inherited MMR defects (1). Approximately 10 -15% of sporadic CRC display dMMR/MSI, with important prognostic and therapeutic implications for patients (2).Research.

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