Drug Information

Drug (ID: DG02034) and It's Reported Resistant Information

• Name: Pazopanib
• Synonyms: Pazopanib; Pazopanib (GW-786034); 444731-52-6; 5-((4-((2,3-dimethyl-2H-indazol-6-yl)(methyl)amino)pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide; 5-(4-((2,3-dimethyl-2H-indazol-6-yl)(methyl)amino)pyrimidin-2-ylamino)-2-methylbenzenesulfonamide; 5-[[4-[(2,3-dimethylindazol-6-yl)-methyl-amino]pyrimidin-2-yl]amino]-2-methyl-benzenesulfonamide; 790713-33-6; 7RN5DR86CK; CHEBI:71219; DSSTox_CID_28659; DSSTox_GSID_48733; DSSTox_RID_82929; GW 78603; GW 786034; GW-786034; GW786034; MFCD11616589; NCGC00188865-01; UNII-7RN5DR86CK
• Indication:
  In total 1 Indication(s)
  . .; .
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Kidney cancer [ICD-11: 2C90]; [1]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Malignant glioma [ICD-11: 2A00]; [2]
  Kidney cancer [ICD-11: 2C90]; [1]
• Formula: C21H23N7O2S
• IsoSMILES: CC1=C(C=C(C=C1)NC2=NC=CC(=N2)N(C)C3=CC4=NN(C(=C4C=C3)C)C)S(=O)(=O)N
• InChI: CUIHSIWYWATEQL-UHFFFAOYSA-N
• InChIKey: 1S/C21H23N7O2S/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25)
• PubChem CID: 10113978
• ChEBI ID: CHEBI:71219
• INTEDE ID: DR1248

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Kidney cancer [ICD-11: 2C90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Solute carrier family 27 member 3 (SLC27A3) [1]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• 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) [1]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• 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) [1]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• 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.

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-761 [2]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SYO-1 cells; Sarcoma; Homo sapiens (Human); CVCL_7146
• In Vitro Model: HS-SYII cells; Sarcoma; Homo sapiens (Human); CVCL_8719
• In Vitro Model: YaFuSS cells; Sarcoma; Homo sapiens (Human); CVCL_L809
• Experiment for Molecule Alteration: qRT-PCR
• Mechanism Description: We performed a comprehensive analysis of secreted miRNA abundance in pazopanib treated/untreated synovial sarcoma cells from four different cell lines (SYO-1, HS-SYII, 1273/99, and YaFuSS) using microarray technology, and discovered miR-761 in EVs as a potential biomarker of pazopanib-resistance in synovial sarcoma. Furthermore, we showed that miR-761 putatively targeted three proteins, thyroid hormone receptor interactor 6 (TRIP6), lamin A/C (LMNA), and NAD-dependent protein deacetylase sirtuin-3 (SIRT3). Knockdown of any of these proteins was shown in previous studies to confer increased resistance to chemotherapeutic agents. Our findings provide new insight into the potential role of miR-761, an EV-secreted miRNA from synovial sarcoma cells, making it a potential candidate for use in sarcoma therapy in the future.

References

• Ref 1: 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 2: Wnt/Beta-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal TumorMol Cancer Ther. 2017 Sep;16(9):1954-1966. doi: 10.1158/1535-7163.MCT-17-0139. Epub 2017 Jun 13.