EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer. Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer. Improved prime editors enable pathogenic allele correction and cancer modelling in adult mice. Search-and-replace genome editing without double-strand breaks or donor DNA. Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors. Programmable A-to-Y base editing by fusing an adenine base editor with an N-methylpurine DNA glycosylase. Improved cytosine base editors generated from TadA variants. G-to-G♼ base editors developed using CRISPRi screens, target-library analysis, and machine learning.CRISPR C-to-G base editors for inducing targeted DNA transversions in human cells. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Oncogenic context shapes the fitness landscape of tumor suppression. Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing. Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity. Rapid modelling of cooperating genetic events in cancer through somatic genome editing. Inducible in vivo genome editing with CRISPR-Cas9. R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine. In situ CRISPR–Cas9 base editing for the development of genetically engineered mouse models of breast cancer. CRISPR–Cas9 knockin mice for genome editing and cancer modeling. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Genetically engineered mouse models in oncology research and cancer medicine. Capturing cancer evolution using genetically engineered mouse models (GEMMs). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. KRASG12C inhibition with sotorasib in advanced solid tumors. Accelerating discovery of functional mutant alleles in cancer. We believe that this approach will accelerate functional studies of cancer-associated mutations and complex genetic combinations that are challenging to construct with traditional models. With this system, we demonstrate somatic prime editing in vivo using lipid nanoparticles, and we model lung and pancreatic cancer through viral delivery of prime editing guide RNAs or orthotopic transplantation of prime-edited organoids. This model allows rapid, precise engineering of a wide range of mutations in cell lines and organoids derived from primary tissues, including a clinically relevant Kras mutation associated with drug resistance and Trp53 hotspot mutations commonly observed in pancreatic cancer. Here we develop a system for in vivo prime editing by encoding a Cre-inducible prime editor in the mouse germline. Current CRISPR–Cas9 models can expand this fraction but are limited by their reliance on error-prone DNA repair. Genetically engineered mouse models only capture a small fraction of the genetic lesions that drive human cancer. A prime editor mouse to model a broad spectrum of somatic mutations in vivo
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