Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens nominates the Werner Syndrome RecQ helicase as a synthetic lethal target in MMR-deficient tumours
Session type: Poster / e-Poster / Silent Theatre session
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.
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.
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.
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.