ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming

by Selleckchem | Sep 29 2023

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.

Comments:

The study you mentioned explores the potential of targeting FGFR1 as a precision treatment for human T-cell acute lymphoblastic leukemia (T-ALL). FGFR1 abnormalities have been identified in various malignancies, indicating its importance as a therapeutic target. However, drug resistance poses a significant challenge in the treatment of T-ALL.

The researchers found that FGFR1 was upregulated in human T-ALL and was inversely correlated with patient prognosis. By knocking down FGFR1, they observed suppressed growth and progression of T-ALL cells both in laboratory settings (in vitro) and in animal models (in vivo). Despite specifically inhibiting FGFR1 signaling in the early stages using inhibitors AZD4547 and PD-166866, the T-ALL cells exhibited resistance to these inhibitors.

The study delved into the molecular mechanisms underlying the resistance of T-ALL cells to FGFR1 inhibitors. They discovered that the inhibitors significantly increased the expression of ATF4, a major initiator of resistance to FGFR1 inhibitors in T-ALL. The researchers further revealed that FGFR1 inhibitors induced ATF4 expression by enhancing chromatin accessibility and activating translation through the GCN2-eIF2α pathway.

Additionally, ATF4 played a role in remodeling amino acid metabolism by stimulating the expression of several metabolic genes, including ASNS, ASS1, PHGDH, and SLC1A5. This metabolic reprogramming maintained the activation of mTORC1, which contributed to drug resistance in T-ALL cells.

To overcome this obstacle, the researchers explored a combination approach by targeting both FGFR1 and mTOR. They found that the synergistic inhibition of FGFR1 and mTOR exhibited enhanced anti-leukemic efficacy.

In summary, the study highlights the potential of FGFR1 as a therapeutic target in human T-ALL. It reveals that ATF4-mediated amino acid metabolic reprogramming is a key contributor to resistance against FGFR1 inhibitors. Combining FGFR1 and mTOR inhibition may offer a promising strategy to overcome drug resistance in T-ALL therapy.