ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment
Liu, Jiye1; Hideshima, Teru1; Xing, Lijie1,2; Wang, Su3,17; Zhou, Wenrong4; Samur, Mehmet K.1,5; Sewastianik, Tomasz6,7; Ogiya, Daisuke1,18; An, Gang8,9; Gao, Shaobing10; Yang, Li11,12; Ji, Tong13; Bianchi, Giada14; Wen, Kenneth1; Tai, Yu-Tzu1; Munshi, Nikhil1; Richardson, Paul1; Carrasco, Ruben6,15; Cang, Yong16; Anderson, Kenneth C.1
2021
Source PublicationSCIENCE ADVANCES
ISSN2375-2548
Volume7Issue:23
DOI10.1126/sciadv.abg2697
AbstractImmunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor kappa B (NF-kappa B) and extracellular signal-regulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-alpha induces proteasomal degradation of TRAF2, noncanonical NF-kappa B, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.
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Indexed BySCIE
Language英语
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000658757100031
PublisherAMER ASSOC ADVANCEMENT SCIENCE
Original Document TypeArticle
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Cited Times [WOS]:0   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttps://kms.shanghaitech.edu.cn/handle/2MSLDSTB/126995
Collection生命科学与技术学院_特聘教授组_杨力组
生命科学与技术学院_PI研究组_仓勇组
Affiliation1.Harvard Med Sch, Jerome Lipper Multiple Myeloma Ctr, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA;
2.Shandong First Med Univ, Dept Hematol, Shandong Prov Hosp, Jinan 250021, Shandong, Peoples R China;
3.Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA;
4.WuXi AppTec Shanghai Co Ltd, Oncol & Immunol Unit, Res Serv Div, Shanghai 200131, Peoples R China;
5.Harvard TH Chan Sch Publ Hlth, Dept Biostat & Computat Biol, Boston, MA 02115 USA;
6.Harvard Med Sch, Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02215 USA;
7.Inst Hematol & Transfus Med, Dept Expt Hematol, PL-02776 Warsaw, Poland;
8.Chinese Acad Med Sci & Peking Union Med Coll, State Key Lab Expt Hematol, Inst Hematol, Tianjin 300020, Peoples R China;
9.Chinese Acad Med Sci & Peking Union Med Coll, Blood Dis Hosp, Tianjin 300020, Peoples R China;
10.Zhengzhou Univ, Affiliated Canc Hosp, Zhengzhou 450008, Peoples R China;
11.Zhejiang Univ, Sch Med, Affiliated Hosp 1, Multiple Myeloma Treatment Ctr, Hangzhou 310003, Peoples R China;
12.Zhejiang Univ, Sch Med, Affiliated Hosp 1, Bone Marrow Transplantat Ctr, Hangzhou 310003, Peoples R China;
13.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Gen Surg, Sch Med, Hangzhou 310020, Peoples R China;
14.Harvard Med Sch, Brigham & Womens Hosp, Dept Internal Med, Div Hematol, Boston, MA 02115 USA;
15.Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA;
16.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;
17.Vertex Pharmaceut, 50 Northern Ave, Boston, MA 02210 USA;
18.Tokai Univ, Dept Hematol & Oncol, Sch Med, Isehara, Kanagawa 2591193, Japan
Recommended Citation
GB/T 7714
Liu, Jiye,Hideshima, Teru,Xing, Lijie,et al. ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment[J]. SCIENCE ADVANCES,2021,7(23).
APA Liu, Jiye.,Hideshima, Teru.,Xing, Lijie.,Wang, Su.,Zhou, Wenrong.,...&Anderson, Kenneth C..(2021).ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment.SCIENCE ADVANCES,7(23).
MLA Liu, Jiye,et al."ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment".SCIENCE ADVANCES 7.23(2021).
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