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

	BCL-2 inhibitor synergizes with PI3K delta inhibitor and overcomes FLT3 inhibitor resistance in acute myeloid leukaemia
	Yao, Ming-Yue 1,2,3,4; Wang, Ya-Fang3 ; Zhao, Yu3,4 ; Ling, Li-Jun3,4 ; He, Ye 2; Wen, Jie 6; Zheng, Ming-Yue 2,5; Jiang, Hua-Liang1,2,3,4,5 ; Xie, Cheng-Ying 2,5,7
	2022
发表期刊	AMERICAN JOURNAL OF CANCER RESEARCH (IF:3.6[JCR-2023],4.5[5-Year])
ISSN	2156-6976
卷号	12 期号:8
发表状态	已发表
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.
关键词	Acute myeloid leukaemia BCL-2 PI3K delta FLT3 synergistic lethality
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收录类别	SCI ; SCIE
语种	英语
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
WOS类目	Oncology
WOS记录号	WOS:000876706500020
出版者	E-CENTURY PUBLISHING CORP
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/248896
专题	免疫化学研究所_特聘教授组_蒋华良组生命科学与技术学院_博士生
通讯作者	Zheng, Ming-Yue; Jiang, Hua-Liang; Xie, Cheng-Ying
作者单位	1.Univ Sci & Technol China, Affiliated Hosp 1, Anhui Prov Hosp, Div Life Sci & Med, Hefei, Anhui, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 6.Univ Sci & Technol China, Affiliated Hosp 1, Anhui Prov Hosp, Dept Radiol,Div Life Sci & Med, Hefei, Anhui, Peoples R China 7.Lingang Lab, Shanghai 200031, Peoples R China
第一作者单位	免疫化学研究所; 生命科学与技术学院
通讯作者单位	免疫化学研究所; 生命科学与技术学院
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).
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).
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).