구태영 (경희대학교 약학대학)

한빛사논문

조회324

경희대학교 약학대학

Mol. Ther., Available online 25 July 2024 | https://doi.org/10.1016/j.ymthe.2024.07.017 CRISPR-mediated ablation of TP53 and EGFR mutations enhances gefitinib sensitivity and anti-tumor efficacy in a mouse model of lung cancer

A-Rum Yoon ^1,2,3, Soyeon Lee ⁴, Ju Hee Kim¹, Yejin Park ⁴, Taeyoung Koo⁴, Chae-Ok Yun^1,2,3,5

¹Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Republic of Korea

²Institute of Nano Science and Technology (INST), Hanyang University, Seoul, Republic of Korea

³Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul, South Korea

⁴College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea

⁵GeneMedicine Co., Ltd., 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea

Correspondence should be addressed to T.K or C-O. Yun

Abstract

Multiple pathogenic single-nucleotide polymorphism (SNP)s have been identified as contributing factors in the aggravation of cancer prognosis and emergence of drug resistance in various cancers. Here we targeted a mutated EGFR and TP53 oncogene harboring a single-nucleotide missense mutation (EGFR-T790M and TP53-R273H), that associated with gefitinib resistance. Co-delivery of adenine base editor and EGFR and TP53 SNP-specific single-guide RNA via adenovirus resulted in precise correction at the oncogenic mutation site with high accuracy and efficiency in vitro and in vivo. Importantly, compared to a control group treated only with a gefitinib, an EGFR inhibitor, co-treatment of Ad/ABE targeting SNPs in TP53 and EGFR in combination of gefitinib increased the drug sensitivity and suppressed abnormal tumor growth more efficiently. Taken together, these results indicate that ABE-mediated correction of dual oncogenic SNPs can be effective strategy for the treatment of drug-resistant cancers.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-29)
연구진국내 연구진
분야 의약학 > 약학

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