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LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo

文献类型：期刊论文

作者Liu, Yingqiang2,3; Lai, Mengzhen2,3; Li, Shan4; Wang, Yanan3; Feng, Fang3; Zhang, Tao3; Tong, Linjiang3; Zhang, Mengge1,3; Chen, Hao4; Chen, Yi1,3
刊名CANCER SCIENCE
出版日期2021-12-16
页码12
关键词C797S epidermal growth factor receptor fourth-generation EGFR TKI non-small cell lung cancer osimertinib resistance
ISSN号1347-9032
DOI10.1111/cas.15229
通讯作者Ding, Ke(dingke@jnu.edu.cn) ; Yu, Ker(keryu@fudan.edu.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Ding, Jian(jding@simm.ac.cn)
英文摘要With the wide clinical use of the third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC), acquired resistance caused by EGFR C797S tertiary mutation has become a concern. Therefore, fourth-generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS-106 as a novel EGFR inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo. In cell-free assay, LS-106 potently inhibited the kinase activities of EGFR(19del/T790M/C797S) and EGFR(L858R/T790M/C797S) with IC50 values of 2.4 nmol/L and 3.1 nmol/L, respectively, which was more potent than osimertinib. Meanwhile, LS-106 exhibited comparable kinase inhibitory effect to osimertinib on EGFR(L858R/T790M) and wild-type EGFR. Results from cellular experiments demonstrated that LS-106 potently blocked the phosphorylation of EGFR C797S triple mutations in the constructed BaF3 cells that highly expressed EGFR(19del/T790M/C797S) or EGFR(L858R/T790M/C797S), and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR(19del/T790M/C797S) (named PC-9-OR cells) using the CRISPR/Cas9 system and found that LS-106 markedly suppressed the activation of EGFR(19del/T790M/C797S) and the proliferation of PC-9-OR cells. Moreover, cells harboring EGFR(19del/T790M/C797S) underwent remarkable apoptosis upon LS-106 treatment. In vivo experiments further demonstrated that oral administration of LS-106 caused significant tumor regression in a PC-9-OR xenograft model, with a tumor growth inhibition rate (TGI) of 83.5% and 136.6% at doses of 30 and 60 mg/kg, respectively. Taken together, we identified LS-106 as a novel fourth-generation EGFR inhibitor against C797S mutation and confirmed its preclinical antitumor effects in C797S-triple-mutant tumor models.
WOS关键词CELL LUNG-CANCER ; ADVANCED NSCLC ; SUBSEQUENT TREATMENT ; ACQUIRED-RESISTANCE ; OPEN-LABEL ; MUTATION ; T790M ; OSIMERTINIB ; GEFITINIB ; PHARMACOKINETICS
资助项目National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2019ZX09301157-003] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2019ZX09301157-004] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020112] ; National Natural Science Foundation of China[81903638] ; National Natural Science Foundation of China[21807045] ; National Natural Science Foundation of China[81922062]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000730669000001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/299232]  
专题新药研究国家重点实验室
通讯作者Ding, Ke; Yu, Ker; Xie, Hua; Ding, Jian
作者单位1.Univ Chinese Acad Sci, Beijing, Peoples R China
2.Fudan Univ, Sch Pharm, Dept Pharmacol, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai, Peoples R China
4.Jinan Univ, Sch Pharm, Int Cooperat Lab Tradit Chinese Med Modernizat &, Chinese Minist Educ MOE, Guangzhou, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Zhongshan Inst Drug Discovery, Zhongshan, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Yingqiang,Lai, Mengzhen,Li, Shan,et al. LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo[J]. CANCER SCIENCE,2021:12.
APA Liu, Yingqiang.,Lai, Mengzhen.,Li, Shan.,Wang, Yanan.,Feng, Fang.,...&Ding, Jian.(2021).LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo.CANCER SCIENCE,12.
MLA Liu, Yingqiang,et al."LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo".CANCER SCIENCE (2021):12.

入库方式： OAI收割

来源：上海药物研究所

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