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Combined inhibition of PI3K delta and FLT3 signaling exerts synergistic antitumor activity and overcomes acquired drug resistance in FLT3-activated acute myeloid leukemia

文献类型：期刊论文

作者He, Ye1,2; Sun, Liping1; Xu, Yongping1; Fu, Li1; Li, Yun1; Bao, Xubin1; Fu, Haoyu1; Xie, Chengying1; Lou, Liguang1
刊名CANCER LETTERS
出版日期2018
卷号420页码:49-59
关键词Acute myeloid leukemia FLT3 PI3K delta CAL101 Synergistic effect
ISSN号0304-3835
DOI10.1016/j.canlet.2018.01.071
文献子类Article
英文摘要PI3K delta and FLT3 are frequently activated in acute myeloid leukemia (AML) and have been implicated as potential therapeutic targets. In this report, we demonstrate that combined inhibition of PI3K delta and FLT3 exerts synergistic antitumor activity in FLT3-activated AML Synergistic antiproliferative effects were observed in FLT3-activated MV-4-11 and EOL-1 AML cell lines, but not in FLT3-independent RS4;11 and HEL cells, as demonstrated by both pharmacological inhibition and silencing of PI3K delta/FLT3. Combined treatment with PI3K delta and FLT3 inhibitors more effectively inhibited ART and ERK phosphorylation, and induced apoptosis more efficiently than either agent alone. This synergistic effect was confirmed in hematopoietic 32D cells transfected with an FLT3-ITD mutant, but not FLT3 wild type. In in vivo FLT3-activated AML xenografts, a PI3K delta inhibitor CAL101 combined with FLT3 inhibitor led to significantly enhanced antitumor activity compared with either agent alone, in association with simultaneous inhibition of AKT and ERK. Importantly, CAL101 combined with FLT3 inhibitors overcame acquired drug resistance in FLT3-ITD AML cells. Thus, combined inhibition of PI3K delta and FLT3 may be a promising strategy in FLT3-activated AML, particularly for patients with FLT3-inhibitor-resistant mutations. (C) 2018 Elsevier B.V. All rights reserved.
WOS关键词HUMAN HEMATOLOGIC MALIGNANCIES ; TYROSINE KINASE ; THERAPEUTIC TARGET ; P110-DELTA ISOFORM ; CELL-PROLIFERATION ; ITD MUTATIONS ; AML ; ACTIVATION ; PI3K ; PROTEIN
资助项目National Natural Science Foundation of China[30801404] ; National Natural Science Foundation of China[81273546] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2013ZX09102008] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2013ZX09402102-001-004]
WOS研究方向Oncology
语种英语
WOS记录号WOS:000428098200005
出版者ELSEVIER IRELAND LTD
源URL[http://119.78.100.183/handle/2S10ELR8/272326]  
专题药理学第一研究室
通讯作者Xie, Chengying; Lou, Liguang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 He, Ye,Sun, Liping,Xu, Yongping,et al. Combined inhibition of PI3K delta and FLT3 signaling exerts synergistic antitumor activity and overcomes acquired drug resistance in FLT3-activated acute myeloid leukemia[J]. CANCER LETTERS,2018,420:49-59.
APA He, Ye.,Sun, Liping.,Xu, Yongping.,Fu, Li.,Li, Yun.,...&Lou, Liguang.(2018).Combined inhibition of PI3K delta and FLT3 signaling exerts synergistic antitumor activity and overcomes acquired drug resistance in FLT3-activated acute myeloid leukemia.CANCER LETTERS,420,49-59.
MLA He, Ye,et al."Combined inhibition of PI3K delta and FLT3 signaling exerts synergistic antitumor activity and overcomes acquired drug resistance in FLT3-activated acute myeloid leukemia".CANCER LETTERS 420(2018):49-59.

入库方式： OAI收割

来源：上海药物研究所

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