Disease Information

General Information of the Disease (ID: DIS00536)

• Name: Kidney cancer
• ICD: ICD-11: 2C90

Type(s) of Resistant Mechanism of This Disease

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

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

Resveratrol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Sirtuin 3 (SIRT3) [1]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Resveratrol
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.47E-39; Fold-change: -9.88E-01; Z-score: -1.66E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• In Vitro Model: Hk-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RPTEC cells; Kidney; Homo sapiens (Human); N.A.
• In Vitro Model: SIRT3-overexpressing 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: SIRT3-overexpressing Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: qRT-PCR and western blotting
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The expression of SIRT3 improves mitochondrial function and biogenesis. Furthermore, the anti-proliferative effects of SIRT3 and RSV are increased in ccRCC through metabolic reprogramming.

Approved Drug(s) 2 drug(s) in total

Pazopanib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Solute carrier family 27 member 3 (SLC27A3) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Pazopanib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.32E-27; Fold-change: 4.34E-01; Z-score: 1.28E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: JAK-STAT signaling pathway; Activation; hsa04630
• Cell Pathway Regulation: Insulin resistance; Activation; hsa04931
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: 769-P cells with SLC27A3 up-regulation; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: 786-O cells with SLC27A3 up-regulation; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for beta-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid beta-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC.

Key Molecule: Solute carrier family 27 member 3 (SLC27A3) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Pazopanib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.32E-27; Fold-change: 4.34E-01; Z-score: 1.28E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAK-STAT signaling pathway; Activation; hsa04630
• Cell Pathway Regulation: Insulin resistance; Activation; hsa04931
• In Vivo Model: Patients with lower SLC27A3 expression; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Overall survival assay (OS); Progression-free interval assay (PFI); Disease-specific survival assay (DSS)
• Mechanism Description: SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for beta-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid beta-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC.

Key Molecule: Solute carrier family 27 member 3 (SLC27A3) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Pazopanib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.32E-27; Fold-change: 4.34E-01; Z-score: 1.28E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAK-STAT signaling pathway; Activation; hsa04630
• Cell Pathway Regulation: Insulin resistance; Activation; hsa04931
• In Vivo Model: Patients with higher SLC27A3 expression; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Overall survival assay (OS); Progression-free interval assay (PFI); Disease-specific survival assay (DSS)
• Mechanism Description: SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for beta-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid beta-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC.

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) [3]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.76E-14; Fold-change: 5.67E-01; Z-score: 8.53E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Caki1/R cells; Liver; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO5was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells.

Key Molecule: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) [3]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.76E-14; Fold-change: 5.67E-01; Z-score: 8.53E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786O/R cells; Liver; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO4was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells.

Key Molecule: Cluster of differentiation 276 (CD276) [3]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.12E-50; Fold-change: 8.24E-01; Z-score: 2.07E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Caki1/R cells; Liver; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO3was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells.

Key Molecule: Cluster of differentiation 276 (CD276) [3]

• Metabolic Type: Nucleic acid metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.12E-50; Fold-change: 8.24E-01; Z-score: 2.07E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786O/R cells; Liver; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO2was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells.

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

H-mMnO2

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) [3]

• Metabolic Type: Mitochondrial metabolism
• Sensitive Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Sensitive Drug: H-mMnO2
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.76E-14; Fold-change: 5.67E-01; Z-score: 8.53E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Caki1/R cells; Liver; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO7was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells.

Key Molecule: Cluster of differentiation 276 (CD276) [3]

• Metabolic Type: Nucleic acid metabolism
• Sensitive Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Sensitive Drug: H-mMnO2
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Clear cell renal cell carcinoma
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.12E-50; Fold-change: 8.24E-01; Z-score: 2.07E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786O/R cells; Liver; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: CD276 and MTHFD2 were identified as a potential surface marker and a therapeutic target, respectively, for targeting sunitinib-resistant ccRCC and its CSC population. MTHFD2 knockdown remodeled the folate-nucleotide metabolism of tumor cells. Moreover, H-mMnO6was confirmed to be able of altering GABA metabolism by enhancing GABA catabolism in drug-resistant tumor cells.

References

• Ref 1: Mitochondrial metabolic reprogramming by SIRT3 regulation ameliorates drug resistance in renal cell carcinoma. PLoS One. 2022 Jun 7;17(6):e0269432.
• Ref 2: STAT2/SLC27A3/PINK1-Mediated Mitophagy Remodeling Lipid Metabolism Contributes to Pazopanib Resistance in Clear Cell Renal Cell Carcinoma. Research (Wash D C). 2024 Nov 26;7:0539.
• Ref 3: Engineered Biomimetic Nanovesicles Synergistically Remodel Folate-Nucleotide and gamma-Aminobutyric Acid Metabolism to Overcome Sunitinib-Resistant Renal Cell Carcinoma. ACS Nano. 2024 Oct 8;18(40):27487-27502.