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Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis

文献类型：期刊论文

作者Tang, Shuai3,4,5; Duan, Yichen4,5; Yuan, Tao2; Hu, Yutinh1,5; Yuan, Liang4; Shen, Ning4; Fu, Yixian4; Pu, Congying4; Wang, Xiaomin4; Xu, Jun4
刊名PHARMACOLOGICAL RESEARCH
出版日期2023-11-01
卷号197页码:12
ISSN号1043-6618
关键词KRAS Pancreatic ductal adenocarcinoma MAPK pathway Tetrandrine TRAIL Death receptors
DOI10.1016/j.phrs.2023.106955
通讯作者Geng, Meiyu(mygeng@simm.ac.cn) ; Huang, Min(mhuang@simm.ac.cn)
英文摘要Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies lacking effective therapies. KRAS mutations that occur in over 90% of PDAC are major oncogenic drivers of PDAC. The MAPK signaling pathway plays a central role in KRAS-driven oncogenic signaling. However, pharmacological inhibitors of the MAPK pathway are poorly responded in KRAS-mutant PDAC, raising a compelling need to understand the mechanism behind and to seek new therapeutic solutions. Herein, we perform a screen utilizing a library composed of 800 naturally-derived bioactive compounds to identify natural products that are able to sensitize KRAS-mutant PDAC cells to the MAPK inhibition. We discover that tetrandrine, a natural bisbenzylisoquinoline alkaloid, shows a synergistic effect with MAPK inhibitors in PDAC cells and xenograft models. Mechanistically, pharmacological inhibition of the MAPK pathway exhibits a double-edged impact on the TRAIL-death receptor axis, transcriptionally upregulating TRAIL yet downregulating its agonistic receptors DR4 and DR5, which may explain the limited therapeutic outcomes of MAPK inhibitors in KRAS-mutant PDAC. Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.
WOS关键词I DOSE-ESCALATION ; CELL LUNG-CANCER ; INDUCED APOPTOSIS ; ACQUIRED-RESISTANCE ; SURFACE EXPRESSION ; ERK INHIBITION ; PHASE-II
资助项目National Natural Science Foundation of China[82225046] ; National Natural Science Foundation of China[81821005] ; National Natural Science Foundation of China[22337004] ; National Natural Science Foundation of China[91957126] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020230] ; Program of Shanghai Academic Research Leader[20XD1424800] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-D-202004]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
WOS记录号WOS:001097132400001
源URL[http://119.78.100.183/handle/2S10ELR8/307628]  
专题新药研究国家重点实验室
通讯作者Geng, Meiyu; Huang, Min
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai 201203, Peoples R China
2.Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Tang, Shuai,Duan, Yichen,Yuan, Tao,et al. Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis[J]. PHARMACOLOGICAL RESEARCH,2023,197:12.
APA Tang, Shuai.,Duan, Yichen.,Yuan, Tao.,Hu, Yutinh.,Yuan, Liang.,...&Huang, Min.(2023).Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis.PHARMACOLOGICAL RESEARCH,197,12.
MLA Tang, Shuai,et al."Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis".PHARMACOLOGICAL RESEARCH 197(2023):12.

入库方式： OAI收割

来源：上海药物研究所

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