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 / G. Picco, C.M. Cattaneo, E.J. van Vliet, G. Crisafulli, G. Rospo, S. Consonni, S.F. Vieira, I. Sanchez Rodriguez, C. Cancelliere, R. Banerjee, L.J. Schipper, D. Oddo, K.K. Dijkstra, J. Cinatl, M. Michaelis, F. Yang, C.M.N. Uk Group, F. Di Nicolantonio, A. Sartore-Bianchi, S. Siena, S. Arena, E.E. Voest, A. Bardelli, M.J. Garnett. - In: CANCER DISCOVERY. - ISSN 2159-8274. - (2021). [Epub ahead of print] [10.1158/2159-8290.CD-20-1508]

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

A. Sartore-Bianchi;S. Siena;
2021

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.
Werner helicase; mismatch repair; colorectal cancer; immunotherapy; drug resistance; targeted therapy; chemotherapy
Settore MED/06 - Oncologia Medica
9-apr-2021
Article (author)
File in questo prodotto:
File Dimensione Formato  
2021 Picco G et al, Cancer Discovery.pdf

embargo fino al 09/04/2021

Tipologia: Post-print, accepted manuscript ecc. (versione accettata dall'editore)
Dimensione 2.68 MB
Formato Adobe PDF
2.68 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/836316
Citazioni
  • ???jsp.display-item.citation.pmc??? 12
  • Scopus 21
  • ???jsp.display-item.citation.isi??? 14
social impact