Werner helicase is a synthetic-lethal vulnerability in Mismatch Repair-Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy and Immunotherapy

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 primary or secondary resistance, as well as by 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 over 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 primary and acquired resistance to clinically relevant targeted therapy, chemotherapy, and immune checkpoint blockade retain WRN dependency. These data show the potential of therapeutically targeting WRN in most dMMR/MSI-H CRC patients, and support the development of WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies.