Drug Information

Drug (ID: DG00250) and It's Reported Resistant Information

• Name: Sunitinib
• Synonyms: Sunitanib; Sunitinibum; Sutent; PDGF TK antagonist; SU 11248; SU11248; KS-5022; SU-11248; SU-11248J; SU-12662; Su-011248; Sunitinib (INN); Sunitinib (free base); Sutent (TN); N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide; N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide; 5-(5-FLUORO-2-OXO-1,2-DIHYDRO-INDOL-3-YLIDENEMETHYL)-2,4-DIMETHYL-1H-PYRROLE-3-CARBOXYLIC ACID (2-DIETHYLAMINO-ETHYL)-AMIDE; Sunitinib (Pan-TK inhibitor)
• Indication:
  In total 2 Indication(s)
  Gastrointestinal stromal tumour [ICD-11: 2B5B]; Approved; [1]
  Malignant digestive organ neoplasm [ICD-11: 2C11]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (5 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [2]
  Colon cancer [ICD-11: 2B90]; [3]
  Gastrointestinal cancer [ICD-11: 2B5B]; [4]
  Kidney cancer [ICD-11: 2C90]; [5]
  Metastatic liver cancer [ICD-11: 2D80]; [6]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Kidney cancer [ICD-11: 2C90]; [7]
• Target: Vascular endothelial growth factor receptor 2 (KDR); VGFR2_HUMAN; [1]
• Formula: C22H27FN4O2
• IsoSMILES: CCN(CC)CCNC(=O)C1=C(NC(=C1C)/C=C\\2/C3=C(C=CC(=C3)F)NC2=O)C
• InChI: 1S/C22H27FN4O2/c1-5-27(6-2)10-9-24-22(29)20-13(3)19(25-14(20)4)12-17-16-11-15(23)7-8-18(16)26-21(17)28/h7-8,11-12,25H,5-6,9-10H2,1-4H3,(H,24,29)(H,26,28)/b17-12-
• InChIKey: WINHZLLDWRZWRT-ATVHPVEESA-N
• PubChem CID: 5329102
• ChEBI ID: CHEBI:38940
• TTD Drug ID: D0R0MW
• VARIDT ID: DR00454
• DrugBank ID: DB01268

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

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

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Platelet-derived growth factor receptor beta (PDGFRB) [5]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Renal cell carcinoma
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.34E-01; Fold-change: 2.84E-02; Z-score: 2.17E-01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance.

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [5]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Renal cell carcinoma
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.44E-02; Fold-change: 4.10E-01; Z-score: 2.85E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance.

Key Molecule: Hepatocyte growth factor receptor (MET) [9]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Renal cancer
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.88E-02; Fold-change: 7.68E-02; Z-score: 2.45E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: STAT3/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: 771R-luc cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA. Here we identified an LncRNA, named lncARSR (LncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response.

Key Molecule: Tyrosine-protein kinase UFO (AXL) [9]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Renal cancer
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.15E-02; Fold-change: 1.30E-01; Z-score: 3.05E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: STAT3/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: 771R-luc cells; Kidney; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA. Here we identified an LncRNA, named lncARSR (LncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response.

Key Molecule: AT-rich interactive domain-containing protein 1A (ARID1A) [11]

• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Renal cancer
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.33E-04; Fold-change: -1.74E-01; Z-score: -5.03E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Chemoresistance; Activation; hsa05207
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis; Immunohistochemical staining assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR144-3p promotes cell proliferation, metastasis, sunitinib resistance in clear cell renal cell carcinoma by downregulating ARID1A. and the downregulation of ARIDIA could promote the function of mir144-3p in cell proliferation, metastasis and chemoresistance.

Key Molecule: Phosphatase and tensin homolog (PTEN) [1]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-130b promoted cell growth and was associated with sunitinib resistance through regulating PTEN expression.

Key Molecule: VEGF-2 receptor (KDR) [20]

• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1alpha/VEGFA/VEGFR signalling pathway; Regulation; N.A.
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1.

Key Molecule: Vascular endothelial growth factor receptor 1 (FLT1) [20]

• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1alpha/VEGFA/VEGFR signalling pathway; Regulation; N.A.
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our study is the first to identify that AUY922 can enhance the sensitivity of ccRCC to sunitinib. AUY922 not only has an inhibitory effect on ccRCC cells, but also enhances the inhibitory effect of sunitinib on ccRCC cells. Additionally, our research is the first to explore the mechanism of AUY922 in ccRCC, demonstrating that it targets the HIF-1/VEGFA/VEGFR pathway by inhibiting HSP90B1.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) [8]

• Metabolic Type: Mitochondrial 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: 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) [8]

• Metabolic Type: Mitochondrial 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: 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) [8]

• Metabolic Type: Nucleic acid 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: 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) [8]

• Metabolic Type: Nucleic acid 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: 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.

Key Molecule: Mesoderm induction early response 2 (MIER2) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Patients with renal cell carcinoma who underwent partial or radical nephrectomy; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Overall survival assay (OS); Disease-free survival assay (DFS)
• Mechanism Description: Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC.

Key Molecule: Phosphoserine aminotransferase 1 (PSAT1) [16]

• Metabolic Type: Amino acid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: 4-week-old malenude mice, SN12; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Mechanism Description: Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT5 increased the susceptibility of sunitinib-resistant cells.

Key Molecule: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC2 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC.

Key Molecule: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OS-RC-2 cells; Kidney; Homo sapiens (Human); CVCL_E313
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC4 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC.

Key Molecule: Mesoderm induction early response 2 (MIER2) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 7Su3rd cells; Kidney; Homo sapiens (Human); N.A.
• In Vitro Model: CaSu3rd cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC.

Key Molecule: Mesoderm induction early response 2 (MIER2) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC1 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC.

Key Molecule: Mesoderm induction early response 2 (MIER2) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC3 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC.

Key Molecule: Phosphoserine aminotransferase 1 (PSAT1) [16]

• Metabolic Type: Amino acid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT1 increased the susceptibility of sunitinib-resistant cells.

Key Molecule: Phosphoserine aminotransferase 1 (PSAT1) [16]

• Metabolic Type: Amino acid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A-498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT2 increased the susceptibility of sunitinib-resistant cells.

Key Molecule: Phosphoserine aminotransferase 1 (PSAT1) [16]

• Metabolic Type: Amino acid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SN12-PM6 cells; N.A.; Homo sapiens (Human); CVCL_9549
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT3 increased the susceptibility of sunitinib-resistant cells.

Key Molecule: Phosphoserine aminotransferase 1 (PSAT1) [16]

• Metabolic Type: Amino acid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293 T cells; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT4 increased the susceptibility of sunitinib-resistant cells.

Key Molecule: Alanine-serine-cysteine transporter 2 (ASCT2) [17]

• Metabolic Type: Redox metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In all three cell lines, qRT-PCR and Western blotting also showed overexpression of ASCT2 in sunitinib-resistant cells compared to sunitinib-sensitive cells (Figure 2a). When comparing the expression of ASCT2 among sunitinib-sensitive cells, ASCT2 was found to be highly expressed in 786-O compared to that in Caki-1 and ACHN (Figure 2a). Sunitinib-resistant cells had higher intracellular concentrations of glutamine metabolism (glutamine, glutamate, and alphaKG)

Key Molecule: Alanine-serine-cysteine transporter 2 (ASCT2) [17]

• Metabolic Type: Redox metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In all three cell lines, qRT-PCR and Western blotting also showed overexpression of ASCT2 in sunitinib-resistant cells compared to sunitinib-sensitive cells (Figure 2a). When comparing the expression of ASCT2 among sunitinib-sensitive cells, ASCT2 was found to be highly expressed in 786-O compared to that in Caki-1 and ACHN (Figure 3a). Sunitinib-resistant cells had higher intracellular concentrations of glutamine metabolism (glutamine, glutamate, and alphaKG)

Key Molecule: Mesoderm induction early response 2 (MIER2) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: 4-week-old nude mice, with Caki-1 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay; Tumor weight assay
• Mechanism Description: Specifically, overexpression of MIER2 plays a pivotal role in enhancing lipid accumulation, promoting malignancy, and contributing to sunitinib resistance in RCC. This occurs through thedownregulationof PGC1A via the MIER2/HDAC1/P53 axis. Our findings highlight the potential significance of targeting HDAC1, and we propose that TSA, an HDAC5 inhibitor, may serve as a promising therapeutic compound for patients with sunitinib-resistant advanced RCC.

Key Molecule: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) [18]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB3 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression.

Key Molecule: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) [18]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB4 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression.

Key Molecule: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) [18]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB5 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression.

Key Molecule: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) [18]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB6 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression.

Key Molecule: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) [18]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB7 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression.

Key Molecule: 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) [18]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hk-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: In view of renal cancer as a metabolic disease [4], PFKFB3 mediated glycolytic pathways should affect RCC development and progression. However, the regulating role of PFKFB3 in RCC glycolysis metabolism is rarely elucidated currently, much less in pRCC. Our study primarily demonstrated the abnormal expression profile of PFKFB3 in pRCC. Experimental assays further verified that PFKFB8 could promote renal cancer cell proliferation and migration in vitro, confirming its oncogenic potential in tumor progression.

Key Molecule: Mesoderm induction early response 2 (MIER2) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• 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: OS-RC-2 cells; Kidney; Homo sapiens (Human); CVCL_E313
• In Vitro Model: Sunitinib-resistant 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: Sunitinib-resistant Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Dose-response curve assay; CCK8 proliferation assay
• Mechanism Description: Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC.

Key Molecule: Mesoderm induction early response 2 (MIER2) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: MIER2 overexpression mice; control mice; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Mechanistically, MIER2 facilitated P53 deacetylation by binding to HDAC1. Acetylation modification augmented the DNA-binding stability and transcriptional function of P53, while deacetylation of P53 hindered the transcriptional process of PGC1A, leading to intracellular lipid accumulation in RCC.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: SET and MYND domain containing 2 (SMYD2) [10]

• Resistant Disease: Kidney cancer [ICD-11: 2C90.1]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Kidney cancer [ICD-11: 2C90]
• The Specified Disease: Renal cancer
• The Studied Tissue: Kidney
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.86E-01; Fold-change: 4.00E-03; Z-score: 1.47E-01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: SMYD2 is a histone methyltransferase.The estimated IC50 values of cisplatin, doxorubicin, or 5-FU (but not docetaxel) for AZ505-treated RCC cells were significantly lower than those for the control cells, indicating that the SMYD2 inhibition enhanced the drug sensitivity in renal cancer cells.

Key Molecule: hsa-mir-130b [1]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-130b promoted cell growth and was associated with sunitinib resistance through regulating PTEN expression.

Key Molecule: hsa-miR-144-3p [11]

• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Chemoresistance; Activation; hsa05207
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR144-3p promotes cell proliferation, metastasis, sunitinib resistance in clear cell renal cell carcinoma by downregulating ARID1A. and the downregulation of ARIDIA could promote the function of mir144-3p in cell proliferation, metastasis and chemoresistance.

Key Molecule: Long non-protein coding RNA SARCC(SARCC) [7]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell adhesion; Inhibition; hsa04514
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• In Vitro Model: Hk-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: OSRC-2 cells; Kidney; Homo sapiens (Human); CVCL_1626
• In Vitro Model: SW839 cells; Kidney; Homo sapiens (Human); CVCL_3604
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Wound-healing assay; Transwell assay
• Mechanism Description: LncRNA-SARCC bound and destabilized AR protein with an inhibition of AR function, which led to transcriptionally de-repress miR143-3p expression, thus inhibition of its downstream signals including AkT, MMP-13, k-RAS and P-ERk. Increased the expression of LncRNA-SARCC decreased RCC cells resistance to Sunitinib.

Key Molecule: hsa-miR-143-3p [7]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cancer progression; Inhibition; hsa05200
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• In Vitro Model: Hk-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: OSRC-2 cells; Kidney; Homo sapiens (Human); CVCL_1626
• In Vitro Model: SW839 cells; Kidney; Homo sapiens (Human); CVCL_3604
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; RNA pull-down assay; ChIP assay
• Experiment for Drug Resistance: MTT assay; Wound-healing assay; Transwell assay
• Mechanism Description: LncRNA-SARCC bound and destabilized AR protein with an inhibition of AR function, which led to transcriptionally de-repress miR143-3p expression, thus inhibition of its downstream signals including AkT, MMP-13, k-RAS and P-ERk. Increased the expression of LncRNA-SARCC decreased RCC cells resistance to Sunitinib.

Key Molecule: LncRNA regulator of Akt signaling associated with HCC and RCC (LNCARSR) [9]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: STAT3/AKT signaling pathway; Regulation; N.A.
• In Vitro Model: 771R-luc cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR; Northern blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA. Here we identified an LncRNA, named lncARSR (LncRNA Activated in RCC with Sunitinib Resistance), which correlated with clinically poor sunitinib response. lncARSR promoted sunitinib resistance via competitively binding miR-34/miR-449 to facilitate AXL and c-MET expression in RCC cells. Furthermore, bioactive lncARSR could be incorporated into exosomes and transmitted to sensitive cells, thus disseminating sunitinib resistance. Treatment of sunitinib-resistant RCC with locked nucleic acids targeting lncARSR or an AXL/c-MET inhibitor restored sunitinib response.

Key Molecule: hsa-mir-133a [5]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line.

Key Molecule: hsa-miR-484 [5]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line.

Key Molecule: hsa-miR-628-5p [5]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line.

Key Molecule: hsa-mir-942 [5]

• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Caki-2 cells; Kidney; Homo sapiens (Human); CVCL_0235
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-92a [19]

• Resistant Disease: Kidney cancer [ICD-11: 2C90.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: A498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: NC886 also promotes renal cancer cell drug-resistance to Sunitinib or Everolimus by promoting EMT through Rock2 phosphorylation-mediated nuclear translocation of beta-catenin.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-141 [21]

• Sensitive Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• In Vitro Model: UMRC-2 cells; Kidney; Homo sapiens (Human); CVCL_2739
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Compared to good responders, microRNA-141 was significantly down-regulated in tumors of poor responders to sunitinib. This seemed spatially linked toepithelial-to-mesenchymaltransitioninvivo. microRNA-141 down-regulation driven epithelial-to-mesenchymal transition in clear cell renal cell carcinoma was linked to anunfavorable response to sunitinib therapy.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Circ_0072732 [22]

• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hsa_circ_0072732 /miR-548b-3p/ SLC7A11 signaling pathway; Regulation; N.A.
• In Vitro Model: 769-P cells; Kidney; Homo sapiens (Human); CVCL_1050
• 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: OSRC-2 cells; Kideny; Homo sapiens (Human); N.A.
• In Vitro Model: A-498 cells; Kidney; Homo sapiens (Human); CVCL_1056
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: OSRC-2 cells; Kideny; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hsa_circ_0072732 was highly expressed in RCC cells. The silence of Hsa_circ_0072732 could increase RCC sensitivity to sunitinib. Hsa_circ_0072732 contributed to sunitinib chemoresistance by impairing ferroptosis. Hsa_circ_0072732 exerts its function mainly by acting as sponges for miR-548b-3p and regulating the expression SLC7A11.

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835Y
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Deep amplicon sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: In this study, we report the clinical activity of sequential therapy with sorafenib and sunitinib in children with FLT3-ITD-positive AML and the emergence of polyclonal secondary FLT3 TkD mutations during TkI therapy as identified by deep amplicon sequencing.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [12]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.F691
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [12]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D835
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: FISH assay; Comparative genomic hybridization array assay; Single nucleotide polymorphism array assay; PCR; Next-generation sequencing assay; Sanger sequencing assay
• Experiment for Drug Resistance: Southern blot analysis; Spectral karyotyping assay
• Mechanism Description: FLT3-mutated patients treated with AC220, sorafenib, or sunitinib commonly relapse with new, resistant FLT3 D835 or F691 mutations within the preexisting FLT3-ITD allele, and one third of the patients who discontinued therapy for any reason also have acquired such mutations.

Gastrointestinal cancer [ICD-11: 2B5B]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [4]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.N822K
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Computed tomography assay
• Mechanism Description: The sunitinib-resistant liver and peritoneal tumors had different point mutations: T to G and T to A, respectively, although both resulted in an N822k amino acid alteration, indicating the polyclonal evolution of recurrent GISTs.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [13]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D816H
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Next-generation sequencing assay
• Experiment for Drug Resistance: Flow cytometric analysis
• Mechanism Description: While tyrosine ki.se inhibitors have been previously utilized for kIT-altered malig.ncies, this patient's specific mutation (D816H) has been shown to be resistant to both imatinib and sunitinib.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [14]

• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• Molecule Alteration: Missense mutation; p.D842V
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Computerized tomography assay
• Mechanism Description: We were able to identify primary kIT mutations in all plasma samples. Additional mutations, including kIT exon 17 S821F and PDGFRA exon 18 D842V, were detected in the patient-matched plasma samples during follow-up and appeared to result in decreased sensitivity to TkIs. Our results demonstrate an approach by which primary and secondary mutations are readily detected in blood-derived circulating tumor DNA from patients with GIST.

Colon cancer [ICD-11: 2B90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-296 [3]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Response evaluation criteria in solid tumors assay
• Mechanism Description: The patients with decrease in miR-296 at 4 weeks may reflect a more aggressive tumor phenotype with increased metastasis and tumor cell invasiveness. The loss of miR-296 may be one of the mechanisms for primary resistance of colorectal cancer to chemotherapy.

References

• Ref 1: miR-130b Promotes Sunitinib Resistance through Regulation of PTEN in Renal Cell Carcinoma. Oncology. 2019;97(3):164-172. doi: 10.1159/000500605. Epub 2019 Jun 13.
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