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

Taeyoung Koo, A. Rum Yoon, Hee Yeon Cho, Sangsu Bae, Chae Ok Yun, Jin Soo Kim

Research output: Contribution to journalArticlepeer-review

94 Citations (Scopus)

Abstract

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 treatingmutatedEGFR-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 mutationassociated diseases.

Original languageEnglish
Pages (from-to)7897-7908
Number of pages12
JournalNucleic Acids Research
Volume45
Issue number13
DOIs
Publication statusPublished - 1 Jul 2017

Bibliographical note

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© The Author(s) 2017.

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