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Nucleic Acids Res. 2017 Jul 27;45(13):7897-7908. doi: 10.1093/nar/gkx490.

Selective disruption of an oncogenic mutant allele by CRISPR/Cas9 induces efficient tumor regression.

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Center for Genome Engineering, Institute for Basic Science (IBS), Seoul 08826, Korea.
Department of Basic Science, University of Science & Technology, Daejeon 34113, Korea.
Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04763, Korea.
Department of Chemistry, Hanyang University, Seoul 04763, Korea.
Department of Chemistry, Seoul National University, Seoul 08826, Korea.


Approximately 15% of non-small cell lung cancer cases are associated with a mutation in the epidermal growth factor receptor (EGFR) gene, which plays a critical role in tumor progression. With the goal of treating mutated EGFR-mediated lung cancer, we demonstrate the use of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) system to discriminate between the oncogenic mutant and wild-type EGFR alleles and eliminate the carcinogenic mutant EGFR allele with high accuracy. We targeted an EGFR oncogene harboring a single-nucleotide missense mutation (CTG > CGG) that generates a protospacer-adjacent motif sequence recognized by the CRISPR/Cas9 derived from Streptococcus pyogenes. Co-delivery of Cas9 and an EGFR mutation-specific single-guide RNA via adenovirus resulted in precise disruption at the oncogenic mutation site with high specificity. Furthermore, this CRISPR/Cas9-mediated mutant allele disruption led to significantly enhanced cancer cell killing and reduced tumor size in a xenograft mouse model of human lung cancer. Taken together, these results indicate that targeting an oncogenic mutation using CRISPR/Cas9 offers a powerful surgical strategy to disrupt oncogenic mutations to treat cancers; similar strategies could be used to treat other mutation-associated diseases.

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