ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming
Zi-jian Zhang1,
Qi-fang Wu1,
An-qi Ren1,
Qian Chen1,
Jiang-zhou Shi1,
Jia-peng Li1,2,
Xi-yu Liu1,
Zhi-jie Zhang1,
Yu-zhe Tang1,
Yuan Zhao1,
Ning-ning Yao3,4,
Xiao-yu Zhang1,
Chang-peng Liu5,
Ge Dong1,
Jia-xuan Zhao6,
Mei-jun Xu1,
Yun-qiang Yue1,
Jia Hu1,
Fan Sun1,
Yu Liu1,
Qi-lin Ao7,8,
Fu-ling Zhou9,
Hong Wu3,4,
Tong-cun Zhang1,6,
Hai-chuan Zhu1,10,11
1 Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan 430065, China
2 School of Science, Wuhan University of Science and Technology, Wuhan 430065, China
3 Peking-Tsinghua Center for Life Sciences, and Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
4 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China
5 Department of Medical Records, Office for DRGs (Diagnosis Related Groups), Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450003, China
6 Key Lab of Industrial Fermentation Microbiology of the Ministry of Education & Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China
7 Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
8 Department of Pathology, School of Basic Medical Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
9 Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
10 College of Life Science, Wuchang University of Technology, Wuhan 430223, China
11 Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, College of Life Science, Wuchang University of Technology, Wuhan 430223, China
Correspondence to: Tong-cun Zhang: zhangtongcun@wust.edu.cn, Hai-chuan Zhu: zhuhaichuan@wust.edu.cn,
DOI: 10.1038/s41401-023-01108-4
Received: 1 February 2023
Accepted: 9 May 2023
Advance online: 6 June 2023
Abstract
Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti- leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.
Keywords:
T-ALL; FGFR1 inhibitor; AZD4547; PD-166866; drug resistance; ATF4
