CRISPR Screens Single Out WRN

The Werner helicase (WRN) has been on drug developers’ radar in part because mutations in the gene cause a syndrome with increased cancer risk. Now, two comprehensive CRISPR-based genomic screens show that WRN is a vulnerability and potential drug target for cancer cells with microsatellite instability (MSI).

Mathew Garnett, PhD, of the Wellcome Sanger Institute in Cambridge, UK, and colleagues knocked out, one at a time, more than 20,000 genes in 324 cell lines representing 30 cancers. For each cancer cell line, the researchers discovered genes whose loss killed the cells or impaired cell growth. Next, the researchers disqualified genes that were essential across most of the cell lines or that were required by only one cancer type, because normal cells are also likely to depend on these genes.

The team then ranked the targets using criteria such as the effect of the knockout on cellular fitness and the availability of genomic biomarkers, ending up with 628 high-priority targets. Garnett and colleagues further sorted these genes by the feasibility of developing drugs to disrupt them.

Working separately, Francisca Vazquez, PhD, of the Broad Institute of Harvard and MIT in Cambridge, MA, and colleagues were searching for genes whose loss would produce synthetic lethality in cells with defective mismatch repair. These cells develop MSI, which is characterized by susceptibility to mutations.

To identify such genes, the scientists combined data from Project Achilles, which is using CRISPR/Cas9 to screen 517 cancer cell lines, and from Novartis's DRIVE project, an RNAi study of 398 cancer cell lines. The Cancer Dependency Map integrates both datasets, making the analysis easier, says Vazquez.

Both groups zeroed in on WRN. “We were surprised because it had such a profound and specific effect on this subset of cancer cells,” says Garnett. WRN has several functions, but both studies suggest that its helicase activity—key for DNA repair—makes it essential for cells with MSI. The findings should encourage the development of WRN helicase inhibitors, the two groups conclude.

Two other recently published studies, one led by Austrian researchers and another from scientists at IDEAYA Biosciences, also pinpointed WRN. “The relationship between MSI and WRN dependency is very strong, [because] one can find it with different methods,” Vazquez says.

The studies also get high marks from Robert Brosh, PhD, of the National Institute on Aging, whose group has been trying to develop WRN inhibitors. “What's satisfying is that all these groups identified an enzyme we know to be important in DNA metabolism.” But he notes that “we need to nail down the precise WRN helicase–dependent pathway” that protects cells with MSI.

The effect of WRN inhibition on healthy cells is also unknown. Werner syndrome resembles premature aging, and it's possible that targeting WRN could lead to similar symptoms. However, says Vazquez, those symptoms develop over decades, whereas patients would receive treatments for a short time. “Inhibiting only one activity—we are hoping that will not be terribly toxic,” she says.

Besides identifying WRN, the research “establishes a real framework to select the best candidate drug targets that will be necessary for the next wave of precision therapies,” says Garnett. –Mitch Leslie