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

  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

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]

• Molecule Alteration: Missense mutation; p.D835Y
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• 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) [8]

• Molecule Alteration: Missense mutation; p.F691
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• 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) [8]

• Molecule Alteration: Missense mutation; p.D835
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• 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]

• Molecule Alteration: Missense mutation; p.N822K
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• 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) [9]

• Molecule Alteration: Missense mutation; p.D816H
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• 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) [10]

• Molecule Alteration: Missense mutation; p.D842V
• Resistant Disease: Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
• 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]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• 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.

Kidney cancer [ICD-11: 2C90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

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

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

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

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• 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: Hk2 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]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• 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: Hk2 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) [12]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• 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; hsa04210
• Cell Pathway Regulation: STAT3/AKT signaling pathway; Regulation; hsa04550
• 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]

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

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

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

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

Key Molecule: SET and MYND domain containing 2 (SMYD2) [13]

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

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-92a [14]

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

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• 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: AT-rich interactive domain-containing protein 1A (ARID1A) [11]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Clear cell renal cell carcinoma [ICD-11: 2C90.Y]
• 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: Tyrosine-protein kinase UFO (AXL) [12]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• 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; hsa04210
• Cell Pathway Regulation: STAT3/AKT signaling pathway; Regulation; hsa04550
• 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: Hepatocyte growth factor receptor (MET) [12]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Regulation; hsa04210
• Cell Pathway Regulation: STAT3/AKT signaling pathway; Regulation; hsa04550
• 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: Platelet-derived growth factor receptor alpha (PDGFRA) [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• 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 blotting 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 beta (PDGFRB) [5]

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

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-141 [15]

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

References

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