结直肠癌
免疫疗法
微卫星不稳定性
医学
合成致死
癌症研究
靶向治疗
免疫检查点
DNA错配修复
癌症
DNA修复
肿瘤科
内科学
生物
遗传学
等位基因
基因
微卫星
作者
Gabriele Picco,Chiara Cattaneo,Esmée J. van Vliet,Giovanni Crisafulli,Giuseppe Rospo,Sarah Consonni,Sara F Vieira,Íñigo Sánchez Rodríguez,Carlotta Cancelliere,Ruby Banerjee,Luuk J. Schipper,Daniele Oddo,Krijn K. Dijkstra,Jindřich Činátl,Martin Michaelis,Fengtang Yang,Federica Di Nicolantonio,Andrea Sartore‐Bianchi,Salvatore Siena,Sabrina Arena,Emile E. Voest,Alberto Bardelli,Mathew J. Garnett
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2021-04-09
卷期号:11 (8): 1923-1937
被引量:38
标识
DOI:10.1158/2159-8290.cd-20-1508
摘要
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. This article is highlighted in the In This Issue feature, p. 1861
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