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

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.

Artesunate inhibits vasculogenic mimicry in choroidal melanoma through HIF-1 α/ VEGF/PDGF pathway.

Choroidal melanoma (CM), a highly metastatic eye tumor, exhibits vasculogenic mimicry (VM) facilitated by hypoxia-induced angiogenesis. This study explored the inhibitory impact of the anti-malarial drug Artesunate (ART) on CM VM through modulation of the HIF-1α/VEGF/PDGF pathway. Immunohistochemistry (IHC) confirmed VM in CM with elevated VEGF and PDGF expression. Hypoxia promoted CM proliferation, upregulating HIF-1α, VEGF and PDGF. VEGF and PDGF enhanced CM migration, invasion and VM, with HIF-1α playing a crucial role. ART mitigated VM formation by suppressing the HIF-1α/VEGF/PDGF pathway, highlighting its potential as an anti-tumor agent in CM.

Intravitreal injection of conbercept for diabetic macular edema complicated with diabetic nephropathy.

AIM: To observe the therapeutic effect of conbercept on diabetic macular edema (DME) complicated with diabetic nephropathy (DN). METHODS: In this retrospective study, 54 patients (54 eyes) that diagnosed as DME from January 2017 to October 2021 were collected. The patients were divided into two groups: DME patients with DN (25 eyes), and DME patients without DN (29 eyes). General conditions were collected before treatment, laboratory tests include fasting blood glucose, HbA1c, microalbumin/creatinine, serum creatinine. Optical coherence tomography (OCT) was used to check the ellipsoidal zone (EZ) and external limiting membrane (ELM) integrity. Central macular thickness (CMT), best corrected visual acuity (BCVA), and retinal hyperreflective foci (HF) as well as numbers of injections were recorded. RESULTS: There were significant differences between fasting blood glucose, HbA1c, serum creatinine, urinary microalbumin/creatinine, and estimated glomerular filtration rate (eGFR) between the two groups (all P<0.05). EZ and ELM continuity in the DME+DN group was worse than that in the DME group (P<0.05). BCVA (logMAR) in the DME group was significantly better than that in the DME+DN group at the same time points during treatment (all P<0.05). CMT and HF values were significantly higher in the DME+DN group than that in the DME group at the all time points (all P<0.05) and significantly decreased in both groups with time during treatment. At 6mo after treatment, the mean number of injections in the DME+DN and DME group was 4.84±0.94 and 3.79±0.86, respectively. CONCLUSION: Conbercept has a significant effect in short-term treatment of DME patients with or without DN, and can significantly ameliorate BCVA, CMT and the number of HF, treatment efficacy of DME patients without DN is better than that of DME patients with DN.