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• W4313485061 abstract "Abstract Background Abnormalities of FGFR1 have been reported in multiple malignancies, which proposes FGFR1 as a potential target for precision treatment, whereas drug resistance remains a formidable obstacle simultaneously. Methods RNA-seq analysis, mouse tumor models, and flow cytometry were performed to identify that the FGFR1 was a potential target in T-ALL. RNA-seq, ATAC-seq, targeted metabolomics analysis, surface sensing of translation (SUnSET) assay, western blot assays, and qRT-PCR were used to investigate the underlying mechanisms of FGFR1-targeting resistance. Drug screening was conducted to identify a drug combination strategy for overcoming this drug resistance. Results We identified that FGFR1 was observably upregulated in T-ALL and inversely correlated with the prognosis of patients. Functional studies showed that the knockdown of FGFR1 suppressed T-ALL cells growth and progression both in vitro and in vivo . Whereas the human T-ALL cells were resistant to FGFR1 inhibitors. Mechanistically, we identified that ATF4 was markedly upregulated and was a major initiator for T-ALL resistance to FGFR1 inhibitors. Expression of ATF4 was induced by FGFR1 inhibitors through enhancing chromatin accessibility transcriptionally combined with activating translation via the GCN2-eIF2α pathway. Then, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes, and further maintained the activation of mTORC1, which contributed to the drug resistance of malignancies. Moreover, targeting FGFR1 and mTOR exhibited synergistically antileukemic efficacy. Conclusion These findings revealed that FGFR1 was a potential therapeutic target in T-ALL, whereas ATF4-induced amino acid metabolic reprogramming mediated the FGFR1-targeted resistance. Synergistically targeting FGFR1 and mTOR could overcome this obstacle in T-ALL therapy." @default.
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• W4313485061 date "2023-01-04" @default.
• W4313485061 modified "2023-09-27" @default.
• W4313485061 title "ATF4 drives the resistance of T-ALL against FGFR1 inhibitors through amino acid metabolic reprogramming" @default.
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• W4313485061 doi "https://doi.org/10.21203/rs.3.rs-2415441/v1" @default.
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