吉非替尼
细胞凋亡
癌症研究
组蛋白脱乙酰酶抑制剂
表皮生长因子受体
肺癌
表皮生长因子受体抑制剂
生物
组蛋白脱乙酰基酶
分子生物学
医学
受体
组蛋白
病理
生物化学
基因
作者
Sachiko Arai,Shinji Takeuchi,Koji Fukuda,Azusa Tanimoto,Akihiro Nishiyama,Hiroaki Konishi,Akimitsu Takagi,Hiroyuki Takahashi,S. Tiong Ong,Seiji Yano
出处
期刊:The Journal of Medical Investigation
[University of Tokushima Faculty of Medicine]
日期:2020-01-01
卷期号:67 (3.4): 343-350
被引量:2
摘要
Drug-tolerant cells are mediators of acquired resistance. BIM-intron2 deletion polymorphism (BIM-del) is one of the mechanisms underlying the resistance to epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI)-mediated apoptosis that induces drug tolerance. Here, we investigated whether resminostat, a histone deacetylase inhibitor, circumvents BIM-del-associated apoptosis resistance. The human EGFR-mutated non-small cell lung cancer (NSCLC) cell line PC-9 and its homozygous BIM-del-positive variant (PC-9 BIMi2- / -), established by editing with zinc finger nuclease, were used. In comparison with PC-9 cells, PC-9 BIMi2- / - cells were less sensitive to apoptosis mediated by EGFR-TKIs such as gefitinib and osimertinib. The combined use of resminostat and an EGFR-TKI preferentially induced the expression of the pro-apoptotic BIM transcript containing exon 4 rather than that containing exon 3, increased the level of pro-apoptotic BIM protein (BIMEL), and stimulated apoptosis in vitro. In a subcutaneous tumor model derived from PC-9 BIMi2- / - cells, gefitinib monotherapy decreased tumor size but retained residual lesions, indicative of the presence of tolerant cells in tumors. The combined use of resminostat and gefitinib increased BIMEL protein level and induced apoptosis, subsequently leading to the remarkable shrinkage of tumor. These findings suggest the potential of resminostat to circumvent tolerance to EGFR-TKIs associated with BIM deletion polymorphism. J. Med. Invest. 67 : 343-350, August, 2020
科研通智能强力驱动
Strongly Powered by AbleSci AI