Disease Information

General Information of the Disease (ID: DIS00541)

• Name: Mature T-cell lymphoma
• ICD: ICD-11: 2A90

Type(s) of Resistant Mechanism of This Disease

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

PD-166866

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Activating transcription factor 4 (ATF4) [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: T-cell acute lymphoblastic leukemia [ICD-11: 2A90.5]
• Resistant Drug: PD-166866
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: The 6 to 8-week-old NCG mice, with Jurkat-luciferase cell; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cd7 antibody assay
• Mechanism Description: 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-eIF2alpha 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.

Clinical Trial Drug(s) 1 drug(s) in total

AZD-4547

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Activating transcription factor 4 (ATF4) [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: T-cell acute lymphoblastic leukemia [ICD-11: 2A90.5]
• Resistant Drug: AZD-4547
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: The 6 to 8-week-old NCG mice, with Jurkat-luciferase cell; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cd7 antibody assay
• Mechanism Description: 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-eIF2alpha 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.

References

• Ref 1: ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming. Acta Pharmacol Sin. 2023 Nov;44(11):2282-2295.