T790米
奥西默替尼
荧光素酶
癌症研究
转基因
突变体
表皮生长因子受体
基因靶向
生物
转基因小鼠
吉非替尼
癌变
体内
癌症
基因
埃罗替尼
遗传学
转染
作者
Dasom Kim,Wonjun Ji,Dong Ha Kim,Yun Jung Choi,Kyungtaek Im,Chae Won Lee,Jeongin Cho,Joongkee Min,Dong‐Cheol Woo,Chang‐Min Choi,Jae Cheol Lee,Young Hoon Sung,Jin Kyung Rho
标识
DOI:10.1016/j.bbrc.2022.09.104
摘要
Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown dramatic response and improvement in treating lung cancer with mutant EGFR, the emergence of drug resistance remains a major problem. In particular, some mutations including T790 M and C797S have been recognized as mechanisms of acquired resistance because they weaken binding affinity to drugs. To date, many attempts have been made to develop a new drug for overcoming acquired resistance to EGFR-TKIs, including secondary mutations. However, an appropriate animal model to evaluate in vivo efficacy during novel drug development remains lacking. In this study, we generated a novel transgenic mouse model that conditionally expresses human EGFRL858R/T790M/C797S and firefly luciferase using Cas9-mediated homology-independent targeted integration. Using a lung-specific Sftpc-CreERT2 mouse line, we induced expression of both the human EGFRL858R/T790M/C797S transgene and firefly luciferase in the lungs of adult mice. The expression of these genes and lung cancer occurrence was monitored using an in vivo imaging system and magnetic resonance imaging, respectively. Overall, our mouse model can be utilized to develop new drugs for overcoming C797S-mediated resistance to osimertinib; further, such knock-in systems for expressing oncogenes may be applied to study tumorigenesis and the development of other targeted agents.
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