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BCL-2 inhibitor synergizes with PI3K delta inhibitor and overcomes FLT3 inhibitor resistance in acute myeloid leukaemia

文献类型：期刊论文

作者Yao, Ming-Yue4,5,6,7; Wang, Ya-Fang5; Zhao, Yu4,5; Ling, Li-Jun4,5; He, Ye6; Wen, Jie2; Zheng, Ming-Yue3,6; Jiang, Hua-Liang3,4,5,6,7; Xie, Cheng-Ying1,3,6
刊名AMERICAN JOURNAL OF CANCER RESEARCH
出版日期2022
卷号12期号:8页码:3829-3842
关键词Acute myeloid leukaemia BCL-2 PI3K delta FLT3 synergistic lethality
ISSN号2156-6976
通讯作者Zheng, Ming-Yue(myzheng@simm.ac.cn) ; Jiang, Hua-Liang(hljiang@simm.ac.cn) ; Xie, Cheng-Ying(ing818@simm.ac.cn)
英文摘要Inhibitors targeting the antiapoptotic molecule BCL-2 have therapeutic potential for the treatment of acute myeloid leukaemia (AML); however, BCL-2 inhibitors such as venetoclax exhibit limited monotherapy efficacy in relapsed or refractory human AML. PI3K delta/AKT signalling has been shown to be constitutively active in AML patients. Here, we demonstrate that the combination of BCL-2 and PI3K delta inhibitors exerts synergistic antitumour effects both in vitro and in vivo in AML. Cotreatment with venetoclax and the specific PI3K delta inhibitor idelalisib significantly enhanced antiproliferative effects and induced caspase-dependent apoptosis in a panel of AML cell lines. The synergistic effects were mechanistically based on the inactivation of AKT/4E-BP-1 signalling and the reduction of MCL-1 expression, which diminished the binding of Bim to MCL-1. Notably, compared with the parental FLT3-ITD-positive MV-4-11, the acquired FLT3 inhibitor quizartinib-resistant xenograft model carrying the F691L mutation, exhibited a markedly higher sensitivity to venetoclax. Furthermore, venetoclax combined with idelalisib led to tumour regression in all animals in this quizartinib-resistant AML model. Thus, these data indicate that combined inhibition of BCL-2 and PI3K delta may be a promising strategy in AML, especially for patients with FLT3-ITD and/or FLT3-TKD mutations.
WOS关键词CELL-PROLIFERATION ; P110-DELTA ISOFORM ; DRUG-RESISTANCE ; PI3K ISOFORM ; MCL-1 ; AML ; VENETOCLAX ; ACTIVATION ; ABT-199 ; TARGET
资助项目Natural Science Foundation of Shanghai[19ZR1467700] ; Lingang Laboratory[LG202101-01-06] ; Major Research Plan of the National Natural Science Foundation of China[91953203]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000876706500020
出版者E-CENTURY PUBLISHING CORP
源URL[http://119.78.100.183/handle/2S10ELR8/302993]  
专题中国科学院上海药物研究所
通讯作者Zheng, Ming-Yue; Jiang, Hua-Liang; Xie, Cheng-Ying
作者单位1.Lingang Lab, Shanghai 200031, Peoples R China
2.Univ Sci & Technol China, Affiliated Hosp 1, Anhui Prov Hosp, Dept Radiol,Div Life Sci & Med, Hefei, Anhui, Peoples R China
3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
7.Univ Sci & Technol China, Affiliated Hosp 1, Anhui Prov Hosp, Div Life Sci & Med, Hefei, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Yao, Ming-Yue,Wang, Ya-Fang,Zhao, Yu,et al. BCL-2 inhibitor synergizes with PI3K delta inhibitor and overcomes FLT3 inhibitor resistance in acute myeloid leukaemia[J]. AMERICAN JOURNAL OF CANCER RESEARCH,2022,12(8):3829-3842.
APA Yao, Ming-Yue.,Wang, Ya-Fang.,Zhao, Yu.,Ling, Li-Jun.,He, Ye.,...&Xie, Cheng-Ying.(2022).BCL-2 inhibitor synergizes with PI3K delta inhibitor and overcomes FLT3 inhibitor resistance in acute myeloid leukaemia.AMERICAN JOURNAL OF CANCER RESEARCH,12(8),3829-3842.
MLA Yao, Ming-Yue,et al."BCL-2 inhibitor synergizes with PI3K delta inhibitor and overcomes FLT3 inhibitor resistance in acute myeloid leukaemia".AMERICAN JOURNAL OF CANCER RESEARCH 12.8(2022):3829-3842.

入库方式： OAI收割

来源：上海药物研究所

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