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

Hanlin Wang; Guanghao Luo; Xiaobei Hu; Gaoya Xu; Tao Wang; Minmin Liu; Xiaohui Qiu; Jianan Li; Jingfeng Fu; Bo Feng; Yutong Tu; Weijuan Kan; Chang Wang; Ran Xu; Yubo Zhou; Jianmin Yang; Jia Li

doi:10.1038/s41467-023-37381-4

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

Nat Commun. 2023 Apr 5;14(1):1882. doi: 10.1038/s41467-023-37381-4.

Authors

Hanlin Wang^{1

2

3}, Guanghao Luo^{1

3

4}, Xiaobei Hu^{1

5}, Gaoya Xu^{1

6}, Tao Wang⁷, Minmin Liu^{1

8}, Xiaohui Qiu^{1

5}, Jianan Li^{1

6}, Jingfeng Fu^{1

3}, Bo Feng^{1

9}, Yutong Tu^{1

3}, Weijuan Kan¹, Chang Wang¹, Ran Xu^{1

6}, Yubo Zhou^{10

11

12

13}, Jianmin Yang¹⁴, Jia Li^{15

16

17

18

19

20

21}

Affiliations

¹ State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 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 Chinese Medicine, 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.
¹⁰ State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. ybzhou@simm.ac.cn.
¹¹ University of Chinese Academy of Sciences, Beijing, 100049, China. ybzhou@simm.ac.cn.
¹² Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, 528400, China. ybzhou@simm.ac.cn.
¹³ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. ybzhou@simm.ac.cn.
¹⁴ Department of Hematology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China. chyangjianmin@163.com.
¹⁵ State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jli@simm.ac.cn.
¹⁶ College of Pharmacy, Fudan University, Shanghai, 210023, China. jli@simm.ac.cn.
¹⁷ University of Chinese Academy of Sciences, Beijing, 100049, China. jli@simm.ac.cn.
¹⁸ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China. jli@simm.ac.cn.
¹⁹ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Guangdong, 528400, China. jli@simm.ac.cn.
²⁰ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. jli@simm.ac.cn.
²¹ School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, No.103 Wenhua Road, Shenyang, Liaoning, China. jli@simm.ac.cn.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CCAAT-Enhancer-Binding Protein-alpha / metabolism
Female
Guanfacine* / therapeutic use
Leukemia, Myeloid, Acute* / drug therapy
Mutation
Protein Kinase Inhibitors / pharmacology
fms-Like Tyrosine Kinase 3

Substances

fms-Like Tyrosine Kinase 3
Guanfacine
Protein Kinase Inhibitors
CCAAT-Enhancer-Binding Protein-alpha