Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma

doi:10.1038/s41401-020-00505-3

	Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma
	Zhang, Xiao-tuan 1,2; Hu, Xiao-bei 1; Wang, Han-lin 1,2,3; Kan, Wei-juan 1; Xu, Lei 1,2,4; Wang, Zhi-jia 1,5; Xiang, Yu-qi 1,2,4; Wu, Wen-biao 1,2,6; Feng, Bo 1,5; Li, Jia-nan 1
刊名	ACTA PHARMACOLOGICA SINICA
	2020-08-27
页码	10
关键词	DLBCL BTK inhibitor ibrutinib resistance UPR TUDCA 2-DG
ISSN号	1671-4083
DOI	10.1038/s41401-020-00505-3
通讯作者	Zhou, Yu-bo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn)
英文摘要	Diffuse large B-cell lymphoma (DLBCL) is the most widespread type of non-Hodgkin lymphoma (NHL). As the most aggressive form of the DLBCL, the activated B-cell-like (ABC) subtype is often resistant to standard chemotherapies. Bruton's tyrosine kinase (BTK) inhibitor ibrutinib provides a potential therapeutic approach for the DLBCL but fails to improve the outcome in the phase III trial. In the current study, we investigated the molecular mechanisms underlying ibrutinib resistance and explored new combination therapy with ibrutinib. We generated an ibrutinib-resistant ABC-DLBCL cell line (OCI-ly10-IR) through continuous exposure to ibrutinib. Transcriptome analysis of the parental and ibrutinib-resistant cell lines revealed that the ibrutinib-resistant cells had significantly lower expression of the unfolded protein response (UPR) marker genes. Overexpression of one UPR branch-XBP1s greatly potentiated ibrutinib-induced apoptosis in both sensitive and resistant cells. The UPR inhibitor tauroursodeoxycholic acid (TUDCA) partially reduced the apoptotic rate induced by the ibrutinib in sensitive cells. The UPR activator 2-deoxy-D-glucose (2-DG) in combination with the ibrutinib triggered even greater cell growth inhibition, apoptosis, and stronger calcium (Ca2+) flux inhibition than either of the agents alone. A combination treatment of ibrutinib (15 mg center dot kg(-1)center dot d(-1), po.) and 2-DG (500 mg/kg, po, b.i.d.) synergistically retarded tumor growth in NOD/SCID mice bearing OCI-ly10-IR xenograft. In addition, ibrutinib induced the UPR in the sensitive cell lines but not in the resistant cell lines of the DLBCL. There was also a combined synergistic effect in the primary resistant DLBCL cell lines. Overall, our results suggest that targeting the UPR could be a potential combination strategy to overcome ibrutinib resistance in the DLBCL.
资助项目	Strategic Priority Research Program of the Chinese Academy of Sciences (CAS)[XDA12020208] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[2018ZX09711002-007-001] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[2018ZX09711002-011-011] ; National Natural Science Foundation of China for Innovation Research Group[81821005] ; Shanghai municipal commission of science and technology[19431900700] ; Shanghai municipal commission of science and technology[18431907100] ; Ministry of Science and Technology of the People's Republic of China
WOS关键词	ENDOPLASMIC-RETICULUM STRESS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; BREAST-CANCER ; ER STRESS ; INHIBITION ; EXPRESSION ; BTK ; PATHWAY ; IRE1-ALPHA ; MUTATIONS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000564952200001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/291574]
专题	中国科学院上海药物研究所
通讯作者	Zhou, Yu-bo; Li, Jia
作者单位	1.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China 5.Jiangnan Univ, Sch Pharmaceut Sci, Wuxi 214122, Jiangsu, Peoples R China 6.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Xiao-tuan,Hu, Xiao-bei,Wang, Han-lin,et al. Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma[J]. ACTA PHARMACOLOGICA SINICA,2020:10.
APA	Zhang, Xiao-tuan.,Hu, Xiao-bei.,Wang, Han-lin.,Kan, Wei-juan.,Xu, Lei.,...&Li, Jia.(2020).Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma.ACTA PHARMACOLOGICA SINICA,10.
MLA	Zhang, Xiao-tuan,et al."Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma".ACTA PHARMACOLOGICA SINICA (2020):10.