Disease Information

General Information of the Disease (ID: DIS00517)

• Name: Lung cancer
• ICD: ICD-11: 2C25

Type(s) of Resistant Mechanism of This Disease

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: . [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Fibroblast cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Gefitinib-resistant NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H1975 parental cells; Lung; Homo sapiens (Human); CVCL_1511
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells.

Key Molecule: . [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Resistant Drug: Gefitinib
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vivo Model: NCI-H1975 xenograft-bearing mice; nude mice bearing AR cell subcutaneous xenografts; Mice
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells.

Osimertinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: . [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Resistant Drug: Osimertinib
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Fibroblast cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Gefitinib-resistant NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H1975 parental cells; Lung; Homo sapiens (Human); CVCL_1511
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells.

Key Molecule: . [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Resistant Drug: Osimertinib
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vivo Model: NCI-H1975 xenograft-bearing mice; nude mice bearing AR cell subcutaneous xenografts; Mice
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells.

YN-968D1

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Activating transcription factor 4 (ATF4) [2]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Resistant Drug: YN-968D1
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2alpha/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells.

Epigallocatechin gallate

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: . [1]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Sensitive Drug: Epigallocatechin gallate
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: Fibroblast cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: Gefitinib-resistant NSCLC cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H1975 parental cells; Lung; Homo sapiens (Human); CVCL_1511
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells.

Key Molecule: . [1]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Sensitive Drug: Epigallocatechin gallate
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Insulin signaling pathway; Activation; hsa04910
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vivo Model: NCI-H1975 xenograft-bearing mice; nude mice bearing AR cell subcutaneous xenografts; Mice
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: We found that the combined use of EGFR-TKIs and EGCG significantly reversed the Warburg effect by suppressing glycolysis while boosting mitochondrial respiration, which was accompanied by increased cellular ROS and decreased lactate secretion. The combination effectively activated the AMPK pathway while inhibited both ERK/MAPK and AKT/mTOR pathways, leading to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells.

References

• Ref 1: Epigallocatechin gallate circumvents drug-induced resistance in non-small-cell lung cancer by modulating glucose metabolism and AMPK/AKT/MAPK axis. Phytother Res. 2023 Dec;37(12):5837-5853.
• Ref 2: Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer. Cell Death Dis. 2022 Jul 21;13(7):636.