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.

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

Cattaneo, Chiara Maria;Crisafulli, Giovanni;Rospo, Giuseppe;Cancelliere, Carlotta;Oddo, Daniele;Di Nicolantonio, Federica;Arena, Sabrina;Bardelli, Alberto
Co-last
;
2021-01-01

Abstract

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.
2021
11
8
candisc.1508.2020
1923
https://aacrjournals.org/cancerdiscovery/article/11/8/1923/666232/Werner-Helicase-Is-a-Synthetic-Lethal
Werner helicase, mismatch repair, colorectal cancer, immunotherapy, drug resistance, targeted therapy, chemotherapy.
Picco, Gabriele; Cattaneo, Chiara Maria; van Vliet, Esmee J; Crisafulli, Giovanni; Rospo, Giuseppe; Consonni, Sarah; Vieira, Sara Filipa; Sanchez Rodriguez, Inigo; Cancelliere, Carlotta; Banerjee, Ruby; Schipper, Luuk Johan; Oddo, Daniele; Dijkstra, Krijn Kristian; Cinatl, Jindrich; Michaelis, Martin; Yang, Fengtang; Uk Group, Cell Model Network; Di Nicolantonio, Federica; Sartore-Bianchi, Andrea; Siena, Salvatore; Arena, Sabrina; Voest, Emile E; Bardelli, Alberto; Garnett, Mathew J
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1792657
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