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Prime Editing Technique Holds Promise for Studying Cancer Mutations, Study Shows

A new technique for introducing cancer-associated mutations into mouse models is reported in Nature Biotechnology this week. Genetically engineered mouse models have become an invaluable tool for examining the mechanisms by which cancer drivers promote tumor development and progression in vivo, but generating and maintaining these models is expensive and time consuming. Further, they also only capture a small fraction of the genetic lesions that drive human cancers. While CRISPR-Cas9 tools can speed up mouse model development and expand the number of mutations that can be introduced into the animals, it is limited by its reliance on error-prone DNA repair. To overcome these challenges, a team led by scientists from the Massachusetts Institute of Technology turned to prime editing, a highly specific and versatile gene editing technology that avoids the formation of indel byproducts associated with DNA repair. The researchers developed their model by encoding a Cre-inducible prime editor in the mouse germline, enabling them to precisely engineer a wide range of mutations in cell lines and organoids derived from primary tissues including a clinically relevant KRAS mutation associated with drug resistance. They also created pancreatic organoids with various mutations in the tumor suppressor gene p53. "We believe that this approach will accelerate the functional studies of cancer-associated mutations and complex genetic contributions that are challenging to construct with traditional models," the researchers write.