Arsenic circumvents the gefitinib resistance by binding to P62 and mediating autophagic degradation of EGFR in non-small cell lung cancer

doi:10.1038/s41419-018-0998-7

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Arsenic circumvents the gefitinib resistance by binding to P62 and mediating autophagic degradation of EGFR in non-small cell lung cancer
	Mao, Jianhua 2,3; Ma, Lie 3,4; Shen, Yan 5; Zhu, Kongkai 6; Zhang, Ru 3; Xi, Wenda 1; Ruan, Zheng 2,3; Luo, Cheng6 ; Chen, Zhu 3; Xi, Xiaodong 2,3
刊名	CELL DEATH & DISEASE
	2018-09-20
卷号	9
ISSN号	2041-4889
DOI	10.1038/s41419-018-0998-7
文献子类	Article
英文摘要	Non-small cell lung cancer (NSCLC) is characterized by hyperexpression and/or gain-of-function mutations of the epidermal growth factor receptor (EGFR), resulting in an elevated overall kinase activity. Gefitinib is remarkably effective in patients with the L858R or AE746-A750-mutated of EGFR. However, drug resistance tends to develop because of the emergence of T790M mutation on EGFR. New strategies other than repressing kinase activity are thus required to treat NSCLC, thereby circumventing the resistance. In this study, arsenic trioxide (ATO) at 2 pM significantly inhibited the proliferation of the gefitinib-resistant NCI-H1975 cells of the EGFR L8581V1 790M mutant compared with a modest inhibition in the gefitinib-sensitive HCC827 cells of AE746-A750 mutant and A549 cells of wild-type EGFR. Moreover, ATO significantly inhibited the overall kinase activity of EGFR primarily through quantitatively diminishing the EGFR in NCI-H1975 cells to an extent comparable with that reached by gefitinib in HCC827 cells. Furthermore, ATO promoted autophagic degradation of EGFR in NSCLC cells by directly binding to P62, which interacted with EGFR, preferentially the L8581V1 790M mutant providing a plausible explanation for a more favorable effect of ATO on NOH1975 cells. Accordingly, the effect of ATO was further confirmed in the NSCLC xenograft mouse models. Our results reveal a new target for ATO with a unique molecular mechanism, i.e., ATO suppresses the overall catalytic potential of EGFR, significantly those with the L858R/T790M mutant in NCI-H1975 cells, through an autophagic degradation by interacting with P62. This study potentially offers an innovative therapeutic avenue for the NSCLC with L858R/T790-Mmutated EGFR.
资助项目	National Key Basic Research Program of China[2013CB966800] ; Ministry of Health Grant[201202003] ; Mega-projects of Scientific Research for the 12rd 5-Year Plan[2013ZX09303302] ; National Natural Science Foundation of China[81670127] ; National Natural Science Foundation of China[81101721] ; National Natural Science Foundation of China[81123005] ; Samuel Waxman Cancer Research Foundation Co-Principal Investigator Program[00000000] ; Shanghai Municipal Commission for Rising-Star Program[13QA1402600] ; Science and Technology Commission of Shanghai Municipality[16ZR1421000] ; Science and Technology Commission of Shanghai Municipality[16PJ1406100] ; National Education Ministry for Young Teachers[20100073120095] ; Shanghai Health Bureau[2011Y162] ; Shanghai Municipal Charitable Funds for Cancer Research[00000000]
WOS关键词	TYROSINE KINASE INHIBITORS ; RECEPTOR ; MUTATIONS ; MECHANISMS ; LEUKEMIA ; PML/RARA ; MUTANT ; ONCOPROTEIN ; AZD9291 ; TRIAL
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000446265900024
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279573]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Xi, Xiaodong; Chen, Saijuan
作者单位	1.Shanghai Jiao Tong Univ, Shanghai Inst Hypertens, Ruijin Hosp, Sch Med, Shanghai 200025, Peoples R China 2.Shanghai Jiao Tong Univ, Collaborat Innovat Ctr Hematol, Ruijin Hosp, Sch Med, 197 Ruijin Rd 2, Shanghai 200025, Peoples R China; 3.Shanghai Jiao Tong Univ, Shanghai Inst Hematol, State Key Lab Med Genom, Ruijin Hosp,Sch Med, 197 Ruijin Rd 2, Shanghai 200025, Peoples R China; 4.Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Shanghai 200240, Peoples R China; 5.Shanghai Jiao Tong Univ, Res Ctr Expt Med, Ruijin Hosp, Sch Med, 197 Ruijin Rd 2, Shanghai 200025, Peoples R China; 6.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Mao, Jianhua,Ma, Lie,Shen, Yan,et al. Arsenic circumvents the gefitinib resistance by binding to P62 and mediating autophagic degradation of EGFR in non-small cell lung cancer[J]. CELL DEATH & DISEASE,2018,9.
APA	Mao, Jianhua.,Ma, Lie.,Shen, Yan.,Zhu, Kongkai.,Zhang, Ru.,...&Chen, Saijuan.(2018).Arsenic circumvents the gefitinib resistance by binding to P62 and mediating autophagic degradation of EGFR in non-small cell lung cancer.CELL DEATH & DISEASE,9.
MLA	Mao, Jianhua,et al."Arsenic circumvents the gefitinib resistance by binding to P62 and mediating autophagic degradation of EGFR in non-small cell lung cancer".CELL DEATH & DISEASE 9(2018).