Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance

doi:10.1186/s12943-020-01202-9

	Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance
	Zhang, Tao 1; Qu, Rong 1; Chan, Shingpan 2; Lai, Mengzhen 1,3; Tong, Linjiang 1; Feng, Fang 1; Chen, Hongyu ; Song, Tingting 4; Song, Peiran 1; Bai, Gang1,5,6 ; Liu, Yingqiang 1,3; Wang, Yanan 1; Li, Yan 1; Su, Yi 1; Shen, Yanyan 1; Sun, Yiming 1; Chen, Yi 1; Geng, Meiyu 1; Ding, Ke 2; Ding, Jian 1; Xie, Hua 1
	2020-05-13
发表期刊	MOLECULAR CANCER (IF:27.7[JCR-2023],31.3[5-Year])
EISSN	1476-4598
卷号	19 期号:1
发表状态	已发表
DOI	10.1186/s12943-020-01202-9
摘要	Background Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFR (T790M) mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR (T790M) and their new resistance mechanisms have attracted much attention. Methods We examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan. Results We identified compound ASK120067 as a novel inhibitor of EGFR (T790M), with selectivity over EGFR (WT). ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFR (T790M) (NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFR (WT). Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFR (T790M). The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo. Conclusions Our results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.
关键词	Non-small cell lung cancer (NSCLC) EGFR T790M Small-molecule inhibitor Drug resistance Ack1
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
资助项目	"Personalized Medicines-Molecular Signature-based Drug Discovery and Development", Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020112][XDA12020209] ; National Natural Science Foundation of China[21702075][81903638] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2019ZX09301157-004] ; Guangdong Natural Science Funds[2017A030310253]
WOS研究方向	Biochemistry & Molecular Biology ; Oncology
WOS类目	Biochemistry & Molecular Biology ; Oncology
WOS记录号	WOS:000536208200001
出版者	BMC
WOS关键词	LUNG-CANCER ; C797S MUTATION ; ACK1 ; AZD9291 ; AMPLIFICATION ; EMERGENCE ; MECHANISM ; ERLOTINIB
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/121531
专题	生命科学与技术学院_博士生
通讯作者	Ding, Ke; Ding, Jian; Xie, Hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Jinan Univ, Guangzhou City Key Lab Precis Chem Drug Dev, Int Cooperat Lab Tradit Chinese Med Modernizat &, Sch Pharm,Chinese Minist Educ MOE, 601 Huangpu Ave West, Guangzhou 510632, Peoples R China 3.Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China 4.Jiangsu Aosaikang Pharmaceut Co Ltd ASK Pharm, 699 Kejian Rd, Nanjing 211112, Peoples R China 5.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Tao,Qu, Rong,Chan, Shingpan,et al. Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance[J]. MOLECULAR CANCER,2020,19(1).
APA	Zhang, Tao.,Qu, Rong.,Chan, Shingpan.,Lai, Mengzhen.,Tong, Linjiang.,...&Xie, Hua.(2020).Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance.MOLECULAR CANCER,19(1).
MLA	Zhang, Tao,et al."Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance".MOLECULAR CANCER 19.1(2020).