Research Highlights

TARGETED THERAPIES . They also all found that the activity of WRN, but not its activity, was required for Prioritizing synthetic lethal targets the synthetic lethal interaction. This dependency seems to hold true in vivo. Behan et al. with functional genomics showed that inducible CRISPR– Cas9-based depletion of WRN The success of the first molecule or antibody target) allowed in established MSI+ HCT116 therapies based on them to identify targets that had colon cancer xenograft tumours (inhibitors of the most potential for novel drug (250–300 mm3) suppressed tumour poly(ADP-ribose) polymerase development (that is, those that are growth. Similarly, Chan et al. found (PARP) in patients with likely to be tractable but against that inducible expression of WRN deficiencies in the homologous which no drugs are currently in short hairpin RNA in KM12 colon recombination (HR) DNA repair preclinical or clinical development). cancer xenograft tumours when pathway) has prompted much From this group, they identified a they reached ~100 mm3 slowed interest in identifying further dependency on WRN associated with tumour growth. synthetic lethal therapeutic the biomarker of MSI, which most Why might MSI+ cells depend on targets. Leveraging the commonly occurs in colon, gastric, WRN? Chan et al., Kategaya et al. power of large-scale endometrial and ovarian cancers. and Lieb et al. presented evidence Credit: Simon Bradbrook/Springer Nature Limited Nature Bradbrook/Springer Simon Credit: cancer cell line Interestingly, three other groups also that WRN depletion increased DNA screens and functional recently identified this dependency double-strand breaks and/or induced genomics, four papers using cancer cell line screens. cell cycle arrest and apoptosis now report Chan et al. searched two in MSI+ cells. Therefore, WRN that cancer large-scale cancer dependency helicase activity might be essential cells with high databases derived from CRISPR–Cas9 to maintain DNA integrity in microsatellite and RNA interference (RNAi) MMR-deficient cells. However, this instability (MSI), screens to investigate their hypothesis synthetic lethal interaction is specific, which arises owing to that MMR-deficient MSI+ tumours as depletion of other RecQ defects in DNA mismatch might have specific vulnerabilities. does not have the same effect. repair (MMR), are selectively This analysis found that in MSI+ cells, Chan et al. and Lieb et al. further vulnerable to knockout of WRN, compared with microsatellite stable found that restoration of MLH1 a RecQ family DNA helicase that (MSS) cells, the top scoring (and thus MMR) only partially could potentially be targeted with was WRN. rescued WRN dependency, and small molecules. Kategaya et al. used a candidate Kategaya et al. showed that MLH1 Behan et al. set out to improve the gene approach to examine whether re-expression at least partially prioritization of potential therapeutic WRN or another RecQ helicase restored MMR but did not rescue targets identified in functional (BLM) were essential in cancer WRN knockdown. This may be genomic screens. They used data cells with defects in various DNA related to irreversible genomic from genome-scale CRISPR–Cas9 repair pathways. Knockdown of alterations that followed MLH1 loss screens (targeting ~18,000 ) both WRN and MLH1 (which is initially, and the full mechanisms conducted in 324 cell lines from part of the MMR pathway) was explaining the interactions between 30 cancer types and developed a synergistic in a non-small-cell lung the MMR pathway and WRN must statistical method to identify genes cancer cell line. still be elucidated. that were essential for fitness in all Lieb et al. noted that the same Regardless, these papers support cancer cells (core fitness genes) or RNAi screen used by Chan et al. further preclinical investigation of that were context-specific fitness had identified that some cancer WRN as a target in MSI+ cancers and genes. The authors then used this cell lines are dependent on WRN, the development of small molecules information to create a database but the mechanism was unknown. that target its helicase activity. called Project Score (https://score. They developed an algorithm Sarah Seton-Rogers

depmap.sanger.ac.uk/) to identify to classify WRN-dependent and Original articles Behan, F. M. et al. vulnerabilities in cancer cells that WRN-independent cell lines, Prioritization of cancer therapeutic targets using could be targeted therapeutically. which identified that WRN CRISPR–Cas9 screens. Nature https://doi.org/ they identified 10.1038/s41586-019-1103-9 (2019) | Chan, E. M. Ranking of targets was based dependency negatively correlated et al. WRN helicase is a synthetic lethal target a dependency not only on evidence from the with MLH1 expression. in microsatellite unstable cancers. Nature CRISPR–Cas9 screens, but also To look more closely at the https://doi.org/10.1038/s41586-019-1102-x on WRN (2019) | Kategaya, L. et al. + associated with included data on whether a genetic identified dependency of MSI helicase is required for the survival of cancer biomarker (for example, genetic cancer cells on WRN, all four cells with microsatellite instability. iScience the biomarker https://doi.org/10.1016/j.isci.2019.02.006 (2019) | driver events or MSI) was associated groups further validated the WRN Lieb, S. et al. is a + of MSI with dependency on a target. dependency in MSI but not in selective vulnerability of microsatellite instability- Further assessments of tractability MSS cell lines derived from colon, high tumor cells. eLife https://doi.org/10.7554/ eLife.43333.001 (2019) (how suitable a is as a small gastric, endometrial and/or ovarian

Nature Reviews | Cancer volume 19 | JUNE 2019 | 305