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Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia

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机构： [1]State key Laboratory of Drug Research, Shanghai Institute ofMateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China [2]College of Pharmacy, Fudan University, Shanghai 210023, China [3]University of Chinese Academy of Sciences, Beijing 100049, China [4]School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310000, China [5]Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong 528400, China [6]School of Chinese Materia Medica, Nanjing University of ChineseMedicine, Nanjing 210023, China [7]Department of Hematology, Changhai Hospital, Naval Medical University, Shanghai 200433, China [8]School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, China [9]School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103 Wenhua Road, Shenyang, Liaoning, China.

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The outcomes of FLT3-ITD acute myeloid leukaemia (AML) have been improved since the approval of FLT3 inhibitors (FLT3i). However, approximately 30-50% of patients exhibit primary resistance (PR) to FLT3i with poorly defined mechanisms, posing a pressing clinical unmet need. Here, we identify C/EBPα activation as a top PR feature by analyzing data from primary AML patient samples in Vizome. C/EBPα activation limit FLT3i efficacy, while its inactivation synergistically enhances FLT3i action in cellular and female animal models. We then perform an in silico screen and identify that guanfacine, an antihypertensive medication, mimics C/EBPα inactivation. Furthermore, guanfacine exerts a synergistic effect with FLT3i in vitro and in vivo. Finally, we ascertain the role of C/EBPα activation in PR in an independent cohort of FLT3-ITD patients. These findings highlight C/EBPα activation as a targetable PR mechanism and support clinical studies aimed at testing the combination of guanfacine with FLT3i in overcoming PR and enhancing the efficacy of FLT3i therapy.© 2023. The Author(s).

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大类 | 1 区

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Q1 MULTIDISCIPLINARY SCIENCES

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Q1 MULTIDISCIPLINARY SCIENCES

影响因子： 14.7 最新[2023版] 16.1 最新五年平均 17.694 出版当年[2021版] 17.764 出版当年五年平均 14.919 出版前一年[2020版] 16.6 出版后一年[2022版]

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第一作者机构： [1]State key Laboratory of Drug Research, Shanghai Institute ofMateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China [2]College of Pharmacy, Fudan University, Shanghai 210023, China [3]University of Chinese Academy of Sciences, Beijing 100049, China

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通讯机构： [1]State key Laboratory of Drug Research, Shanghai Institute ofMateriaMedica, Chinese Academy of Sciences, Shanghai 201203, China [2]College of Pharmacy, Fudan University, Shanghai 210023, China [3]University of Chinese Academy of Sciences, Beijing 100049, China [4]School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310000, China [5]Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong 528400, China [6]School of Chinese Materia Medica, Nanjing University of ChineseMedicine, Nanjing 210023, China [9]School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103 Wenhua Road, Shenyang, Liaoning, China.

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