Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens nominates the Werner Syndrome RecQ helicase as a synthetic lethal target in MMR-deficient tumours


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Gabriele Picco1,Fiona M Behan1,Francesco Iorio1,Emanuel Gonçalves1,Charlotte M Beaver1,Giorgia Migliardi2,Rita Santos3,Yanhua Rao3,Francesco Sassi2,Marika Pinnelli2,Rizwan Ansari1,Sarah Harper1,David Adam Jackson1,Rebecca McRae1,Rachel Pooley1,Piers Wilkinson1,Dieudonne van der Meer1,David Dow3,Carolyn Buser-Doepner3,Andrea Bertotti2,Livio Trusolino2,Euan A. Stronach3,Julio Saez-Rodriguez4,Kosuke Yusa5,Mathew Garnett1
1Wellcome Trust Sanger Institute, Cambridge, UK,2Candiolo Cancer Institute, Strada Provinciale, Italy,3GlaxoSmithKline (GSK), London, UK,4Institute for Computational Biomedicine, Heidelberg University, Heidelberg, Germany,5Stem Cell Genetics, Institute of Frontier Life and Medical Sciences, Kyoto, Japan

Abstract

Background

Microsatellite instability (MSI) is caused by deficient DNA mismatch repair (MMR) and occurs in more than 20 tumour types. MSI is frequent in colon, ovarian, endometrial and gastric cancers. Werner syndrome (WRN) helicase has an important role in maintenance of genome stability, DNA repair, replication and telomere maintenance.

Method

To identify new oncology targets, we performed CRISPR-Cas9 genome-wide screens in 324 human cancer cell lines. Integrating genomic data, biomarker analyses and target tractability, we prioritized over 600 candidate targets which are required for the fitness of cancer cells. 

Results

WRN was selected as a promising new candidate synthetic-lethal target in MSI tumours from multiple cancer types. CRISPR and RNAi-based studies verified that WRN is selectively essential MSI cell lines and dispensable in MSS cancer cell lines. Moreover, we demonstrated that WRN is required to sustain in vivo growth of MSI colorectal cancer (CRC) cells. Mechanistically, the activity of WRN helicase domain is essential for MSI cell viability, and we demonstrated that WRN inhibition in MSI CRC cell lines induces double-stranded DNA breaks that cause massive genome instability, promoting apoptosis both in vitro and in vivo. Finally, we investigated the causal link between MMR-deficiency and WRN-dependency.

Conclusion

Collectively, our study establishes WRN as a synthetic lethal vulnerability in MSI cancers, representing an unexplored opportunity to develop a novel targeted therapy for MSI cancers.