中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance

文献类型：期刊论文

作者Zhang, Tao3; Qu, Rong3; Chan, Shingpan4; Lai, Mengzhen3,5; Tong, Linjiang3; Feng, Fang3; Chen, Hongyu; Song, Tingting1; Song, Peiran3; Bai, Gang2,3,6
刊名MOLECULAR CANCER
出版日期2020-05-13
卷号19期号:1页码:15
关键词Non-small cell lung cancer (NSCLC) EGFR T790M Small-molecule inhibitor Drug resistance Ack1
DOI10.1186/s12943-020-01202-9
通讯作者Ding, Ke(dingke@jnu.edu.cn) ; Ding, Jian(jding@simm.ac.cn) ; Xie, Hua(hxie@simm.ac.cn)
英文摘要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.
WOS关键词LUNG-CANCER ; C797S MUTATION ; ACK1 ; AZD9291 ; AMPLIFICATION ; EMERGENCE ; MECHANISM ; ERLOTINIB
资助项目Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020112] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020209] ; National Natural Science Foundation of China[21702075] ; National Natural Science Foundation of China[81903638] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2019ZX09301157-004] ; Guangdong Natural Science Funds[2017A030310253] ; Special Research Assistant Program of the Chinese Academy of Sciences
WOS研究方向Biochemistry & Molecular Biology ; Oncology
语种英语
WOS记录号WOS:000536208200001
出版者BMC
源URL[http://119.78.100.183/handle/2S10ELR8/280079]  
专题新药研究国家重点实验室
通讯作者Ding, Ke; Ding, Jian; Xie, Hua
作者单位1.Jiangsu Aosaikang Pharmaceut Co Ltd ASK Pharm, 699 Kejian Rd, Nanjing 211112, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.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
5.Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, 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):15.
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),15.
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):15.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。