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Research Using CRISPR to identify a new cancer drug target

3D medical background with DNA strand
Two separate Nature studies have pinpointed WRN as a promising drug target for MSI tumors. (kirstypargeter/iStock/Getty Images Plus/Getty Images)

The CRISRR-Cas9 gene-editing technology is enabling scientists who want to study gene function. Now, with the help of CRISPR, two separate teams of scientists led by the Wellcome Trust Sanger Institute and the Broad Institute have identified key genes essential for cancer survival, making them attractive drug targets.

The Wellcome Sanger-led team used CRISPR-Cas9 to screen over 18,000 genes in more than 300 cancer cell lines from 30 different cancer types. They then developed a computational framework to prioritize the 600 most promising targets for drug development. For its analysis, the Broad Institute-led team examined data from two cancer dependency datasets that screened a total of 915 cell lines.

One target called Werner syndrome RecQ helicase (WRN) stood out for both teams. It’s present in multiple cancer types with a particular DNA defect called microsatellite instability (MSI), according to results published Wednesday in two companion Nature studies here and here.

CRISPR has allowed scientists to probe almost every gene in the human genome to identify those that are crucial to cancer survival or growth. “With CRISPR we have discovered a very exciting opportunity to develop new drugs targeting cancers,” Kosuke Yusa, co-lead author of the Wellcome Sanger study, said in a statement.

Certain tumors are marked by MSI-high, which results when “mismatch repair” genes malfunction and there are abnormal repeated nucleotides in the DNA sequence. These tumors are dependent on WRN to survive, the teams found.

That makes WRN a promising therapeutic target in MSI cancers. The teams believe that mutations in the mismatch repair gene, combined with inhibition of the WRN-encoding gene, could lead to cancer cell death.

MSI has been seen in many cancer types, including 15% of colon cancers, 22% of gastric tumors, at least 20% of endometrial cancers and 12% ovarian cancers. In fact, the first tissue-agnostic FDA approval that went to Merck & Co.’s PD-1 blockbuster Keytruda, which was approved to treat MSI-high cancer regardless of the tumor site. Following that approval, Roche developed a diagnostic test that detects the mismatch repair deficiency biomarker.

“A possible route for clinical development of WRN antagonists would be as an adjunct therapy to approved immune checkpoint inhibitors in MSI tumors,” the Wellcome study authors, including those from GlaxoSmithKline, wrote in the paper.

Both teams fed their findings to a Cancer Dependency Map that the two institutions are building. It offers an atlas that connects tumor features with cancer dependencies to guide the development of precision medicine.

“To give a new drug the best chance of succeeding in the very final phases of clinical trials, it is crucial to select the best and most promising drug target at the beginning of the drug development process,” Francesco Iorio, co-first author of the Wellcome study, said in a statement. “For the first time, in a data-driven way, we provide guidance at a genome-scale on which new therapeutic targets should be put forward for the development of new anti-cancer drugs.”

The Broad Institute-led researchers suggest that further studies will be needed to understand “the intersecting roles of MMR deficiency and genomic lesions in MSI with WRN dependence.”