Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia
文献类型：期刊论文
| 作者 | Chen, Yu-jun6,7; Zhao, Yu6,7; Yao, Ming-yue5; Wang, Ya-fang6; Ma, Ming4,5; Yu, Cheng-cheng5; Jiang, Hua-liang3,6,7 ; Wei, Wu5; Shen, Jie2; Xu, Xiao-wei1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2025-01-30 |
| 页码 | 14 |
| 关键词 | acute myeloid leukemia FLT3 p300/CBP quizartinib resistance combination strategy |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-025-01479-w |
| 通讯作者 | Shen, Jie(shj421@126.com) ; Xu, Xiao-wei(xuxiaowei1616@126.com) ; Xie, Cheng-ying(xiecy@lglab.ac.cn) |
| 英文摘要 | FMS-like tyrosine kinase-3 (FLT3), a class 3 receptor tyrosine kinase, can be activated by mutations of internal tandem duplication (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3-TKD), leading to constitutive activation of downstream signaling cascades, including the JAK/STAT5, PI3K/AKT/mTOR and RAS/MAPK pathways, which promote the progression of leukemic cells. Despite the initial promise of FLT3 inhibitors, the discouraging outcomes in the treatment of FLT3-ITD-positive acute myeloid leukemia (AML) promote the pursuit of more potent and enduring therapeutic approaches. The histone acetyltransferase complex comprising the E1A binding protein P300 and its paralog CREB-binding protein (p300/CBP) is a promising therapeutic target, but the development of effective p300/CBP inhibitors faces challenges due to inherent resistance and low efficacy, often exacerbated by the absence of reliable clinical biomarkers for patient stratification. In this study we investigated the role of p300/CBP in FLT3-ITD AML and evaluated the therapeutic potential of targeting p300/CBP alone or in combination with FLT3 inhibitors. We showed that high expression of p300 was significantly associated with poor prognosis in AML patients and positively correlated with FLT3 expression. We unveiled that the p300/CBP inhibitors A485 or CCS1477 dose-dependently downregulated FLT3 transcription via abrogation of histone acetylation in FLT3-ITD AML cells; in contrast, the FLT3 inhibitor quizartinib reduced the level of H3K27Ac. Concurrent inhibition of p300/CBP and FLT3 enhanced the suppression of FLT3 signaling and H3K27 acetylation, concomitantly reducing the phosphorylation of STAT5, AKT, ERK and the expression of c-Myc, thereby leading to synergistic antileukemic effects both in vitro and in vivo. Moreover, we found that p300/CBP-associated transcripts were highly expressed in quizartinib-resistant AML cells with FLT3-TKD mutation. Targeting p300/CBP with A485 or CCS1477 retained the efficacy of quizartinib, suggesting marked synergy when combined with p300/CBP inhibitors in quizartinib-resistant AML models, as well as primary FLT3-ITD+ AML samples. These results demonstrate a potential therapeutic strategy of combining p300/CBP and FLT3 inhibitors to treat FLT3-ITD and FLT3-TKD AML. |
| WOS关键词 | DRUG-RESISTANCE ; PI3K-DELTA ; MUTATIONS ; DISCOVERY ; THERAPY ; LIGANDS ; TARGETS ; CBP |
| 资助项目 | ShanghaiTech University[LG202101-01-06] ; Shanghai Municipal Government ; Discovery Technology Platform at the Shanghai Institute for Advanced Immunochemical Studies in ShanghaiTech University |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001409410600001 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/315950]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Shen, Jie; Xu, Xiao-wei; Xie, Cheng-ying |
| 作者单位 | 1.Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Sch Med, Dept Hematol, Shanghai 200080, Peoples R China 2.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Dept Pharm, SATCM Grade Lab Tradit Chinese Med Preparat 3, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai 201203, Peoples R China 4.Shanghai Jiao Tong Univ, Sch Life Sci & Biotechnol, Shanghai 200240, Peoples R China 5.Lingang Lab, Shanghai 200031, Peoples R China 6.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Yu-jun,Zhao, Yu,Yao, Ming-yue,et al. Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia[J]. ACTA PHARMACOLOGICA SINICA,2025:14. |
| APA | Chen, Yu-jun.,Zhao, Yu.,Yao, Ming-yue.,Wang, Ya-fang.,Ma, Ming.,...&Xie, Cheng-ying.(2025).Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia.ACTA PHARMACOLOGICA SINICA,14. |
| MLA | Chen, Yu-jun,et al."Concurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia".ACTA PHARMACOLOGICA SINICA (2025):14. |
入库方式： OAI收割
来源：上海药物研究所
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