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ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid
Zi-Jian Zhang1, Qi-Fang Wu1, An-Qi Ren1
1Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan, 430065, China.
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.
Insights
Fibroblast Growth Factor Receptor 1 (FGFR1) is upregulated in T-cell acute lymphoblastic leukemia (T-ALL). Inhibiting FGFR1 and mTOR shows synergistic anti-leukemic effects, overcoming drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Fibroblast Growth Factor Receptor 1 (FGFR1) abnormalities are implicated in various cancers, positioning it as a potential precision medicine target.
- Drug resistance to FGFR1 inhibitors poses a significant challenge in treating malignancies.
Purpose of the Study:
- To investigate FGFR1 as a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL).
- To elucidate the molecular mechanisms driving T-ALL cell resistance to FGFR1 inhibitors.
Main Methods:
- Examined FGFR1 expression in human T-ALL samples and correlated it with patient prognosis.
- Assessed the effects of FGFR1 knockdown on T-ALL growth in vitro and in vivo.
- Investigated the molecular response of T-ALL cells to FGFR1 inhibitors (AZD4547, PD-166866).
- Analyzed the role of ATF4, the GCN2-eIF2α pathway, and amino acid metabolism in drug resistance.
- Evaluated the synergistic efficacy of combined FGFR1 and mTOR inhibition.
Main Results:
- FGFR1 was significantly upregulated in T-ALL, correlating inversely with patient prognosis.
- FGFR1 knockdown inhibited T-ALL progression.
- T-ALL cells exhibited resistance to FGFR1 inhibitors, mediated by increased ATF4 expression.
- FGFR1 inhibitors induced ATF4 via chromatin accessibility and GCN2-eIF2α pathway activation.
- ATF4 reprogrammed amino acid metabolism, maintaining mTORC1 activation and contributing to resistance.
- Combined FGFR1 and mTOR inhibition demonstrated synergistic anti-leukemic effects.
Conclusions:
- FGFR1 is a viable therapeutic target in human T-ALL.
- ATF4-mediated amino acid metabolic reprogramming is a key mechanism of FGFR1 inhibitor resistance.
- Simultaneous inhibition of FGFR1 and mTOR offers a promising strategy to overcome resistance in T-ALL therapy.
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