Targeted therapy can selectively kill cancer cells without affecting healthy tissue. Choosing good drug targets is an important part of the successful development of such therapies. In recent years, CRISPR has become a unique tool for the discovery of tumor drug targets, which can be used to mutate, inhibit or activate any target human gene.
    Recently, scientists from UK reported a major achievement: Using genome-scale CRISPR-Cas9 screens 18,009 genes in 324 human cancer cell lines from 30 cancer types. They also developed a genetic score calculation framework that prioritizes cancer drug targets, the team finalized 628 priority targets, including pan-cancer target genes and cancer-type specific genes.
    They divided the 628 most promising targets into three groups based on tractability. One group contains 40 promising targets which are approved in anticancer drugs or a target of some drug candidates in clinical or preclinical development stages. Group 2 contains 277 priority targets, and there are currently no drugs targeting these targets in the clinical development phase, but there is evidence to support the operability of these targets. The third group contains 311 priority targets and there is currently no information or lack of information to support their operability.
    Among these targets, WRN (Wernersyndrome RecQ helicase, a helicase that assists cells to replicate or read DNA by unwinding the double helix structure of the genome) has higher operability scores in many different cancer types.
    The study used CRISPR and RNAi technology to investigate nearly a thousand cancer cell lines. It found that 73% of MSI cancer cells are dependent on WRN; in contrast, the effect of MRN deletions on non-MSI cancer cells is minimal. Studies have also found that inhibition of WRN expression can significantly delay the growth of MSI cancer in mice.
    Scientists say that healthy, genetically stable cells are well tolerant of WRN deficiency, suggesting that drugs that block WRN should primarily affect WRN-dependent cancer cells, but are relatively harmless to normal cells. In addition, although hereditary WRN deficiency leads to a disease called Werner syndrome, the appearance of symptoms can take decades. This also suggests that anti-cancer is feasible by interfering with WRN. On the other hand, MSI is clearly a biomarker for targeting WRN therapy. Since there are no drugs that directly target WRN, the researchers hope that this evidence will promote the development of WRN inhibitors for the treatment of MSI-containing tumors.