Picco, Gabriele, Cattaneo, Chiara M., van Vliet, Esmée J., Crisafulli, Giovanni, Rospo, Giuseppe, Consonni, Sarah, Vieira, Sara F., Rodríguez, Iñigo Sánchez, Cancelliere, Carlotta, Banerjee, Ruby, and others. (2021) Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy. Cancer Discovery, . ISSN 2159-8274. E-ISSN 2159-8290. (doi:10.1158/2159-8290.CD-20-1508) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:90386)
| The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication) | |
| Official URL: https://doi.org/10.1158/2159-8290.CD-20-1508 |
Abstract
Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease that is 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 colorectal cancer 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 patients with dMMR/MSI-H colorectal cancer and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies.
Significance: We found that a large, diverse set of dMMR/MSI-H colorectal cancer 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 colorectal cancer tumors as a monotherapy or in combination with targeted agents, chemotherapy, or immunotherapy.
| Item Type: | Article |
|---|---|
| DOI/Identification number: | 10.1158/2159-8290.CD-20-1508 |
| Subjects: |
R Medicine > RC Internal medicine > RC254 Neoplasms. Tumors. Oncology R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Divisions > Division of Natural Sciences > Biosciences |
| Depositing User: | Martin Michaelis |
| Date Deposited: | 27 Sep 2021 18:33 UTC |
| Last Modified: | 05 Nov 2024 12:56 UTC |
| Resource URI: | https://kar.kent.ac.uk/id/eprint/90386 (The current URI for this page, for reference purposes) |
University of Kent Author Information
Michaelis, Martin.
| Creator's ORCID: |
 https://orcid.org/0000-0002-5710-5888
|
|---|---|
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