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.
Subject(s)
Amino Acids , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Humans , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , TOR Serine-Threonine Kinases/metabolism , Signal Transduction , T-Lymphocytes/metabolism , Cell Line, Tumor , Minor Histocompatibility Antigens , Amino Acid Transport System ASC/metabolism , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Activating Transcription Factor 4/metabolismABSTRACT
Oxygen of two propionic acid groups of the heme group in an MP-8 molecule, leading to an increase in the non-planarity of the porphyrin ring of the heme group. The increasing extent in the non-planarity of the porphyrin ring of the heme group due to the interaction of La3+ and MP-8 molecule would be significantly decreased because NaCl could increase the aggregation extent of MP-8 molecules. Although methanol can reduce the aggregation extent of MP-8 molecules, it has little influence on the increasing extent in the non-planarity of the porphyrin ring of the heme group due to the interaction of La3+ and MP-8 molecule.
