@article{APS10923,
author = {Zi-jian Zhang and Qi-fang Wu and An-qi Ren and Qian Chen and Jiang-zhou Shi and Jia-peng Li and Xi-yu Liu and Zhi-jie Zhang and Yu-zhe Tang and Yuan Zhao and Ning-ning Yao and Xiao-yu Zhang and Chang-peng Liu and Ge Dong and Jia-xuan Zhao and Mei-jun Xu and Yun-qiang Yue and Jia Hu and Fan Sun and Yu Liu and Qi-lin Ao and Fu-ling Zhou and Hong Wu and Tong-cun Zhang and Hai-chuan Zhu},
title = {ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming},
journal = {Acta Pharmacologica Sinica},
volume = {44},
number = {11},
year = {2023},
keywords = {},
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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/10923}
}