Efficient Correction of Oncogenic KRAS and TP53 Mutations through CRISPR Base Editing

Research output: Contribution to journalResearch articleContributedpeer-review



KRAS is the most frequently mutated oncogene in human cancer, and its activating mutations represent long-sought therapeutic targets. Programmable nucleases, particularly the CRISPR-Cas9 system, provide an attractive tool for genetically targeting KRAS mutations in cancer cells. Here, we show that cleavage of a panel of KRAS driver mutations suppresses growth in various human cancer cell lines, revealing their dependence on mutant KRAS. However, analysis of the remaining cell population after long-term Cas9 expression unmasked the occurence of oncogenic KRAS escape variants that were resistant to Cas9-cleavage. In contrast, the use of an adenine base editor to correct oncogenic KRAS mutations progressively depleted the targeted cells without the appearance of escape variants and allowed efficient and simultaneous correction of a cancer-associated TP53 mutation. Oncogenic KRAS and TP53 base editing was possible in patient-derived cancer organoids, suggesting that base editor approaches to correct oncogenic mutations could be developed for functional interrogation of vulnerabilities in a personalized manner for future precision oncology applications.

SIGNIFICANCE: Repairing KRAS mutations with base editors can be used for providing a better understanding of RAS biology and may lay the foundation for improved treatments for KRAS-mutant cancers.


Original languageEnglish
Pages (from-to)3002-3015
Number of pages14
JournalCancer research
Issue number17
Publication statusPublished - 2 Sept 2022

External IDs

Scopus 85137080051
unpaywall 10.1158/0008-5472.can-21-2519
Mendeley 8429e19f-278c-3c74-b48d-3b1c1aa7c417


Sustainable Development Goals


  • CRISPR-Cas Systems, Carcinogenesis/genetics, Gene Editing, Humans, Mutation, Neoplasms/genetics, Oncogenes, Precision Medicine, Proto-Oncogene Proteins p21(ras)/genetics, Tumor Suppressor Protein p53/genetics