| Autor: |
Frank Buchholz, Jovan Mircetic, Daniel E. Stange, Duran Sürün, Lukas T. Schmitt, Moustafa Abohawya, Catherine P. Cortés Vesga, Martina Augsburg, Alexander Hennig, Olga A. Sidorova, Shady Sayed |
| Rok vydání: |
2023 |
| DOI: |
10.1158/0008-5472.c.6514029.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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