Molecule Information

General Information of the Molecule (ID: Mol00458)
Name
Mast/stem cell growth factor receptor Kit (KIT) ,Homo sapiens
Molecule Type
Protein
Gene Name
KIT
Gene ID
3815
Location
chr4:54657267-54740783[+]
Sequence
MRGARGAWDFLCVLLLLLRVQTGSSQPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTD
PGFVKWTFEILDETNENKQNEWITEKAEATNTGKYTCTNKHGLSNSIYVFVRDPAKLFLV
DRSLYGKEDNDTLVRCPLTDPEVTNYSLKGCQGKPLPKDLRFIPDPKAGIMIKSVKRAYH
RLCLHCSVDQEGKSVLSEKFILKVRPAFKAVPVVSVSKASYLLREGEEFTVTCTIKDVSS
SVYSTWKRENSQTKLQEKYNSWHHGDFNYERQATLTISSARVNDSGVFMCYANNTFGSAN
VTTTLEVVDKGFINIFPMINTTVFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWE
DYPKSENESNIRYVSELHLTRLKGTEGGTYTFLVSNSDVNAAIAFNVYVNTKPEILTYDR
LVNGMLQCVAAGFPEPTIDWYFCPGTEQRCSASVLPVDVQTLNSSGPPFGKLVVQSSIDS
SAFKHNGTVECKAYNDVGKTSAYFNFAFKGNNKEQIHPHTLFTPLLIGFVIVAGMMCIIV
MILTYKYLQKPMYEVQWKVVEEINGNNYVYIDPTQLPYDHKWEFPRNRLSFGKTLGAGAF
GKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSELKVLSYLGNHMNIVNLLGAC
TIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEAALYKNLLHSKESSCSDSTNE
YMDMKPGVSYVVPTKADKRRSVRIGSYIERDVTPAIMEDDELALDLEDLLSFSYQVAKGM
AFLASKNCIHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVVKGNARLPVKWMAPES
IFNCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMY
DIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSV
GSTASSSQPLLVHDDV
    Click to Show/Hide
Function
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.
    Click to Show/Hide
Uniprot ID
KIT_HUMAN
Ensembl ID
ENSG00000157404
HGNC ID
HGNC:6342
        Click to Show/Hide the Complete Species Lineage
Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens
Type(s) of Resistant Mechanism of This Molecule
  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 Drug
Approved Drug(s)
17 drug(s) in total
Click to Show/Hide the Full List of Drugs
Avapritinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Gastrointestinal stromal tumor [1]
Resistant Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Resistant Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.T670I (c.2009C>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
M230 cells Skin Homo sapiens (Human) CVCL_D749
Experiment for
Molecule Alteration		 PCR
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Gastrointestinal stromal tumor [1]
Resistant Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Resistant Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.V654A (c.1961T>C)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
M230 cells Skin Homo sapiens (Human) CVCL_D749
Experiment for
Molecule Alteration		 PCR
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Solid tumour/cancer [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
M230 cells Skin Homo sapiens (Human) CVCL_D749
Experiment for
Molecule Alteration		 PCR
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Gastrointestinal stromal tumor [1]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.V560D (c.1679T>A)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
M230 cells Skin Homo sapiens (Human) CVCL_D749
Experiment for
Molecule Alteration		 PCR
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Hematologic Cancer [2]
Sensitive Disease Hematologic Cancer [ICD-11: MG24.Y]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Mast cell neoplasm [3]
Sensitive Disease Mast cell neoplasm [ICD-11: 2A21.1]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.V560G (c.1679T>G)
Experimental Note Identified from the Human Clinical Data
Disease Class: Mastocytosis [4]
Sensitive Disease Mastocytosis [ICD-11: 2A21.0]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Synonymous
p.D816D (c.2448C>T)
Experimental Note Identified from the Human Clinical Data
       Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Disease Class: Mast cell leukaemia [5]
Sensitive Disease Mast cell leukaemia [ICD-11: 2A21.2]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.V560G (c.1679T>G)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
M-07e cells Peripheral blood Homo sapiens (Human) CVCL_2106
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
Chinese hamster ovary (CHO)-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Enzyme-linked immunosorbent assay; Cellular proliferation test assay
Disease Class: Mast cell neoplasm [5]
Sensitive Disease Mast cell neoplasm [ICD-11: 2A21.1]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816Y (c.2446G>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
M-07e cells Peripheral blood Homo sapiens (Human) CVCL_2106
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
Chinese hamster ovary (CHO)-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Enzyme-linked immunosorbent assay; Cellular proliferation test assay
Disease Class: Acute myeloid leukemia [5]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
M-07e cells Peripheral blood Homo sapiens (Human) CVCL_2106
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
Chinese hamster ovary (CHO)-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Enzyme-linked immunosorbent assay; Cellular proliferation test assay
Disease Class: Gastrointestinal stromal tumor [5]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Complex-indel
p.W557_V559delinsF (c.1670_1675delGGAAGG)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
M-07e cells Peripheral blood Homo sapiens (Human) CVCL_2106
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
Chinese hamster ovary (CHO)-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Enzyme-linked immunosorbent assay; Cellular proliferation test assay
Disease Class: Gastrointestinal stromal tumor [5]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Avapritinib
 Drug Info 
Molecule Alteration Missense mutation
p.D820V (c.2459A>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
M-07e cells Peripheral blood Homo sapiens (Human) CVCL_2106
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
Chinese hamster ovary (CHO)-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model BALB/c nude mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Enzyme-linked immunosorbent assay; Cellular proliferation test assay
Axitinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [6]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V559D (c.1676T>A)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Solid tumour/cancer [6]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V559A (c.1676T>C)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Solid tumour/cancer [6]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V559G (c.1676T>G)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Solid tumour/cancer [6]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.L576P (c.1727T>C)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Solid tumour/cancer [6]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V654A (c.1961T>C)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Solid tumour/cancer [6]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.T670I (c.2009C>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Solid tumour/cancer [6]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.A829P (c.2485G>C)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Gastrointestinal stromal tumor [6]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.V559D (c.1676T>A)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Gastrointestinal stromal tumor [6]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration IF-deletion
p.V560_Y578del19 (c.1679_1735del57)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Gastrointestinal stromal tumor [6]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Axitinib
 Drug Info 
Molecule Alteration Missense mutation
p.K642E (c.1924A>G)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-882 cells Gastric Homo sapiens (Human) CVCL_7044
GIST-5R cells Gastric Homo sapiens (Human) CVCL_A9M9
GIST-48B cells Gastric Homo sapiens (Human) CVCL_M441
In Vivo Model Female BALB/c-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Whole transcriptome shotgun sequencing assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Cabozantinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [7]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Cabozantinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 32D cells Bone marrow Homo sapiens (Human) CVCL_0118
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.D816V (c.2447A>T) in gene KIT cause the resistance of Cabozantinib by aberration of the drug's therapeutic target
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Gastrointestinal stromal tumor [8]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Duplication
p.A502_Y503 (c.1504_1509)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Clinical GIST specimens .
In Vivo Model NMRI mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Mechanism Description Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. Cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models.
Disease Class: Gastrointestinal stromal tumor [8]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Cabozantinib
 Drug Info 
Molecule Alteration Complex-indel
p.K558_G565delinsR (c.1673_1693del21)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Clinical GIST specimens .
In Vivo Model NMRI mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Mechanism Description Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. Cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models.
Carboplatin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Osteosarcoma [9]
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Resistant Drug Carboplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
MEF2 signaling pathway Regulation hsa04013
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
G-292 cells Bone Homo sapiens (Human) CVCL_2909
SJSA-1 cells Bone Homo sapiens (Human) CVCL_1697
MG63.2 cells Bone Homo sapiens (Human) CVCL_R705
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Cisplatin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Osteosarcoma [9]
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Resistant Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
MEF2 signaling pathway Regulation hsa04013
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
G-292 cells Bone Homo sapiens (Human) CVCL_2909
SJSA-1 cells Bone Homo sapiens (Human) CVCL_1697
MG63.2 cells Bone Homo sapiens (Human) CVCL_R705
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Lung small cell carcinoma [10]
Sensitive Disease Lung small cell carcinoma [ICD-11: 2C25.2]
 Disease Info 
Sensitive Drug Cisplatin
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model H446 cells Lung Homo sapiens (Human) CVCL_1562
H446/CDDP cells Lung Homo sapiens (Human) CVCL_RT21
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 CCK8 assay
Mechanism Description miR-137 was closely related to MDR of SCLC, and interference of miR-137 expression may attenuate drug resistant of H446/CDDP cells to cisplatin, partially through kIT expression regulation. kIT might be only one of the downstream molecules of miR-137 that related to SCLC MDR.
Crizotinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Non-small cell lung cancer [11]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Structural variation
Copy number gain
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Low throughput experiment assay
Experiment for
Drug Resistance		 Progression-free survival assay
Mechanism Description Acquired resistance can occur through failure of drug delivery to the target, as in isolated central nervous system (CNS) progression, or by selection of biological variants during TkI exposure.
Disease Class: Lung adenocarcinoma [12]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816G
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell proliferation Activation hsa05200
Experiment for
Molecule Alteration		 FISH analysis; Sanger sequencing assay; Multiplex single nucleotide base extension assay
Experiment for
Drug Resistance		 MTS cellular proliferation assay
Mechanism Description An activating mutation in the kIT proto-oncogene receptor tyrosine kinase (kIT) (p.D816G) was identified by SNaPshot sequencing in a tumor sample from a patient with ROS1-positive NSCLC identified by fluorescence in situ hybridization whose disease progressed after initial response to crizotinib. kITD816G is an activating mutation that induces autophosphorylation and cell proliferation.
Doxorubicin
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Osteosarcoma [9]
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Resistant Drug Doxorubicin
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
MEF2 signaling pathway Regulation hsa04013
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
G-292 cells Bone Homo sapiens (Human) CVCL_2909
SJSA-1 cells Bone Homo sapiens (Human) CVCL_1697
MG63.2 cells Bone Homo sapiens (Human) CVCL_R705
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Etoposide
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Osteosarcoma [9]
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Resistant Drug Etoposide
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
MEF2 signaling pathway Regulation hsa04013
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
G-292 cells Bone Homo sapiens (Human) CVCL_2909
SJSA-1 cells Bone Homo sapiens (Human) CVCL_1697
MG63.2 cells Bone Homo sapiens (Human) CVCL_R705
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Fluorouracil
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Colorectal cancer [13]
Sensitive Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease Info 
Sensitive Drug Fluorouracil
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
In Vitro Model SW480 cells Colon Homo sapiens (Human) CVCL_0546
DLD1 cells Colon Homo sapiens (Human) CVCL_0248
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 A real-time cell analyzer assay
Mechanism Description c-KIT was shown to mediate chemo-resistance (kike 5-FU) in ovarian tumor initiating cells, miR-34a inhibits Erk signaling and colony formation by down-regulation of c-kit, miR-34a can inhibit this effect via down-regulation of c-kit and therefore sensitize cells to chemotherapeutic treatment.
Gilteritinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Acute myeloid leukemia [2]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug Gilteritinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Hematologic Cancer [2]
Sensitive Disease Hematologic Cancer [ICD-11: MG24.Y]
 Disease Info 
Sensitive Drug Gilteritinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Imatinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Gastrointestinal stromal cancer [14], [15], [16]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D820Y
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Exon sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description KIT and PDGFRA mutation analysis was performed in the primary tumors of 27 patients. Of these, 17 tumors (63%) had primary mutations in kIT exon 11, 4 (15%) had primary mutations in kIT exon 9 mutation, and 6 (22%) wild-type kIT. PDGFRA mutations were not detected in any tumor. After surgery following imatinib treatment, mutation analysis was performed on the responsive and progressive lesions of 17 patients. In addition to the original mutation, one of two patients with FP harbored secondary mutation in kIT exon 17 in the progressive lesion, whereas the second patient had only the original mutation in the progressive lesion. In the five GP patients evaluated, all except one harbored a synchronous secondary mutation in kIT exon 17 in progressive lesions. Surprisingly, one patient harbored a synchronous secondary mutation in kIT exon 17, showing that kIT mutations were present in two different codons of exon 17 in five different progressive lesions. Responsive lesions, however, possessed only their original mutations.
Disease Class: Gastrointestinal stromal cancer [15], [16]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816E
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Exon sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description KIT and PDGFRA mutation analysis was performed in the primary tumors of 27 patients. Of these, 17 tumors (63%) had primary mutations in kIT exon 11, 4 (15%) had primary mutations in kIT exon 9 mutation, and 6 (22%) wild-type kIT. PDGFRA mutations were not detected in any tumor. After surgery following imatinib treatment, mutation analysis was performed on the responsive and progressive lesions of 17 patients. In addition to the original mutation, one of two patients with FP harbored secondary mutation in kIT exon 17 in the progressive lesion, whereas the second patient had only the original mutation in the progressive lesion. In the five GP patients evaluated, all except one harbored a synchronous secondary mutation in kIT exon 17 in progressive lesions. Surprisingly, one patient harbored a synchronous secondary mutation in kIT exon 17, showing that kIT mutations were present in two different codons of exon 17 in five different progressive lesions. Responsive lesions, however, possessed only their original mutations.
Disease Class: Gastrointestinal stromal cancer [15], [17]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T670E
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Bidirectional DNA sequencing assay
Experiment for
Drug Resistance		 Magnetic resonance tomograph assay; Computer-assisted tomography assay
Mechanism Description Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired kIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.
Disease Class: Gastrointestinal stromal cancer [15]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.S709F
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Bidirectional DNA sequencing assay
Experiment for
Drug Resistance		 Magnetic resonance tomograph assay; Computer-assisted tomography assay
Mechanism Description Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired kIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.
Disease Class: Gastrointestinal stromal cancer [18]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816A
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description PFS and OS were longer for patients with secondary kIT exon 13 or 14 mutations (which involve the kIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the kIT activation loop). Biochemical profiling studies confirmed the clinical results. The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.
Disease Class: Gastrointestinal stromal cancer [18], [19], [20]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.A829P
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description PFS and OS were longer for patients with secondary kIT exon 13 or 14 mutations (which involve the kIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the kIT activation loop). Biochemical profiling studies confirmed the clinical results. The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.
Disease Class: Gastrointestinal stromal cancer [21]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
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.
Disease Class: Gastrointestinal stromal cancer [17]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.Y578C
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
Mechanism Description Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.
Disease Class: Gastrointestinal stromal cancer [17]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Frameshift mutation
p.V569_Y578del
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
Mechanism Description Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.
Disease Class: Gastrointestinal stromal cancer [17]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.N680K
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
Mechanism Description Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.
Disease Class: Gastrointestinal stromal cancer [17]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.K818_D820>N
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
Mechanism Description Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.
Disease Class: Gastrointestinal stromal cancer [17]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Frameshift mutation
p.D579del
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Quantitative immunohistochemistry assay; Massively parallel sequencing approach assay; Sanger sequencing assay
Mechanism Description Although we achieved a sufficiently high level of sensitivity, neither in the primary FFPE nor in the fresh-frozen GISTs we were able to detect pre-existing resistant subclones of the corresponding known secondary resistance mutations of the recurrent tumours. This supports the theory that secondary kIT resistance mutations develop under treatment by "de novo" mutagenesis. Alternatively, the detection limit of two mutated clones in 10,000 wild-type clones might not have been high enough or heterogeneous tissue samples, per se, might not be suitable for the detection of very small subpopulations of mutated cells.
Disease Class: Gastrointestinal stromal cancer [22]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D820V
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Sanger sequencing assay; Exome sequencing assay; Microarray transcription analysis
Experiment for
Drug Resistance		 Overall survival assay
Mechanism Description Sanger sequencing revealed that R8 harbored kIT D820Y and R9 had kIT D820V as secondary kIT mutations.
Disease Class: Gastrointestinal stromal cancer [23]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.S821F
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.
Disease Class: Gastrointestinal stromal cancer [14], [15], [24]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T670I
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST882 cells Gastric Homo sapiens (Human) CVCL_7044
293T cells Breast Homo sapiens (Human) CVCL_0063
GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 DNA sequencing assay
Experiment for
Drug Resistance		 In situ Cell Death Detection assay
Mechanism Description We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of kIT protein expression. We demonstrate downregulation of kIT transcription as an underlying mechanism for bortezomib-mediated inhibition of kIT expression. Collectively, our results show that inhibition of the proteasome using bortezomib can effectively kill imatinib-sensitive and imatinib-resistant GIST cells in vitro and provide a rationale to test the efficacy of bortezomib in GIST patients. Bortezomib has a dual mode of action against GIST cells involving upregulation of pro-apoptotic histone H2AX and downregulation of oncogenic kIT.
Disease Class: Gastrointestinal stromal cancer [14], [15], [24]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.V654A
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
Mechanism Description Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.
Disease Class: Gastrointestinal stromal cancer [14], [15], [25]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.Y823D
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
PI3K/AKT signaling pathway Activation hsa04151
In Vitro Model GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
Mechanism Description Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.
Disease Class: Gastrointestinal stromal cancer [17], [19], [25]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.N822Y
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
Mechanism Description Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.
Disease Class: Gastrointestinal stromal cancer [14], [15], [24]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.N822K
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
Mechanism Description Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.
Disease Class: Gastrointestinal stromal cancer [15], [16], [25]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D820G
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
Mechanism Description Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.
Disease Class: Gastrointestinal stromal cancer [25], [18]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D820A
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
Mechanism Description Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.
Disease Class: Gastrointestinal stromal cancer [19], [25], [26]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816H
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
Mechanism Description Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.
Disease Class: Gastrointestinal stromal cancer [16], [25], [26]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.C809G
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
In Vitro Model GIST48 cells Gastric Homo sapiens (Human) CVCL_7041
GIST430 cells Colon Homo sapiens (Human) CVCL_7040
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography (D-HPLC) screening assay; Automated sequencing assay
Mechanism Description Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical kIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on kIT kinase activity for activation of critical downstream signaling pathways. Comparable findings were obtained after kIT shRNA knockdown in GIST430 cells, demonstrating that activation of proliferation/survival signaling pathways remains kIT dependent in this imatinib-resistant cell line. kIT knockdown in the cell lines also induced flow-cytometric evidence for G1 block, decreased S phase, and markedly increased apoptosis.
Disease Class: Gastrointestinal stromal cancer [15], [24], [25]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D820E
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography assay; Direct sequencing assay
Experiment for
Drug Resistance		 Computerized tomography/positron emission tomography imaging assay
Mechanism Description This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.
Disease Class: Gastrointestinal stromal cancer [24]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816G
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography assay; Direct sequencing assay
Experiment for
Drug Resistance		 Computerized tomography/positron emission tomography imaging assay
Mechanism Description This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.
Disease Class: Gastrointestinal stromal cancer [24]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D716N
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography assay; Direct sequencing assay
Experiment for
Drug Resistance		 Computerized tomography/positron emission tomography imaging assay
Mechanism Description This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.
Disease Class: Gastrointestinal stromal cancer [24]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D820Y
Experimental Note Identified from the Human Clinical Data
In Vitro Model 293T cells Breast Homo sapiens (Human) CVCL_0063
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Denaturing high-performance liquid chromatography assay; Direct sequencing assay
Experiment for
Drug Resistance		 Computerized tomography/positron emission tomography imaging assay
Mechanism Description This study shows the high frequency of kIT/PDGFRA kinase domain mutations in patients with secondary resistance and defines genomic amplification of kIT/PDGFRA as an alternative cause of resistance to the drug. In a subset of patients, cancer cells lost their dependence on the targeted tyrosine kinase. Our findings show the sensitivity of the imatinib-resistant kIT-T670I and kIT-V654A and of PDGFRA-D842V mutants to PkC412.
Disease Class: Renal cell carcinoma [27]
Resistant Disease Renal cell carcinoma [ICD-11: 2C90.0]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Dimerisation
Up-regulation
Experimental Note Identified from the Human Clinical Data
In Vitro Model HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Flow cytometry
Mechanism Description These results demonstrated that the c-kit mutation drove auto-dimerisation, and promoted receptor phosphorylation, and ligand-independent receptor signalling pathway. Therefore, dimerisation is the common step in both the activation processes of KIT prior to phosphorylation and therefore, blocking receptor dimerisation may be more effective than blocking the phosphorylated receptor.
Disease Class: Gastrointestinal stromal tumor [27]
Resistant Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Dimerisation
Up-regulation
Experimental Note Identified from the Human Clinical Data
In Vitro Model 5 GIST tissues .
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Flow cytometry
Mechanism Description These results demonstrated that the c-kit mutation drove auto-dimerisation, and promoted receptor phosphorylation, and ligand-independent receptor signalling pathway. Therefore, dimerisation is the common step in both the activation processes of KIT prior to phosphorylation and therefore, blocking receptor dimerisation may be more effective than blocking the phosphorylated receptor.
       Regulation by the Disease Microenvironment (RTDM) Click to Show/Hide
Disease Class: Gastrointestinal stromal cancer [28], [17]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.K642E
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation PI3K/AKT signaling pathway Activation hsa04151
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay
Mechanism Description Secondary kIT mutations were identified in 11/14 (78.6%) imatinib-acquired-resistance patients, with nine patients in kIT gene exon17, and the other two in exon 13. The expressions of p-kIT, p-AkT, PCNA and BCL-2 were higher in the samples of imatinib-resistant GISTs than those of imatinib-responsive ones. P-kIT, p-AkT expressions were higher in imatinib acquired-resistance GISTs with secondary kIT mutations than imatinib-responsive ones with primary mutation. Total kIT, MAPk, p-MAPk, p-MTOR expressions were comparable in all varied GISTs.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Gastrointestinal stromal tumor [29]
Resistant Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
Cell viability Activation hsa05200
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
GIST882 cells Gastric Homo sapiens (Human) CVCL_7044
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK8 assay; EdU assay; Flow cytometry assay
Mechanism Description CCDC26 knockdown enhanced imatinib resistance in GIST cells and c-kIT knockdown reversed the imatinib resistance mediated by CCDC26 inhibition.
Methotrexate
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Osteosarcoma [9]
Resistant Disease Osteosarcoma [ICD-11: 2B51.0]
 Disease Info 
Resistant Drug Methotrexate
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
MEF2 signaling pathway Regulation hsa04013
In Vitro Model MG63 cells Bone marrow Homo sapiens (Human) CVCL_0426
SAOS-2 cells Bone marrow Homo sapiens (Human) CVCL_0548
U2OS cells Bone Homo sapiens (Human) CVCL_0042
G-292 cells Bone Homo sapiens (Human) CVCL_2909
SJSA-1 cells Bone Homo sapiens (Human) CVCL_1697
MG63.2 cells Bone Homo sapiens (Human) CVCL_R705
MNNG/HOS cells Bone Homo sapiens (Human) CVCL_0439
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.
Midostaurin
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [1]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
M230 cells Skin Homo sapiens (Human) CVCL_D749
Experiment for
Molecule Alteration		 PCR
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Mast cell neoplasm [3]
Sensitive Disease Mast cell neoplasm [ICD-11: 2A21.1]
 Disease Info 
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.V560G (c.1679T>G)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Disease Class: Acute myeloid leukemia [3]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Disease Class: Acute myeloid leukemia [2]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Hematologic Cancer [2]
Sensitive Disease Hematologic Cancer [ICD-11: MG24.Y]
 Disease Info 
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Mast cell leukaemia [30]
Sensitive Disease Mast cell leukaemia [ICD-11: 2A21.2]
 Disease Info 
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.S476I (c.1427G>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Bone marrow .
Experiment for
Molecule Alteration		 Histologic and immunophenotypic analysis
Experiment for
Drug Resistance		 Examination of bone marrow smears assay
Disease Class: Mast cell neoplasm [3]
Sensitive Disease Mast cell neoplasm [ICD-11: 2A21.1]
 Disease Info 
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.D816Y (c.2446G>T)
Experimental Note Identified from the Human Clinical Data
Disease Class: Systemic mastocytosis [31]
Sensitive Disease Systemic mastocytosis [ICD-11: 2A21.3]
 Disease Info 
Sensitive Drug Midostaurin
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Identified from the Human Clinical Data
Nilotinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Gastrointestinal stromal cancer [32]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Nilotinib
 Drug Info 
Molecule Alteration Missense mutation
p.N655T
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Gene mutation analysis assay
Experiment for
Drug Resistance		 Computed tomography assay
Mechanism Description According to gene mutation analysis, the resistant GIST contained not only the primary genetic kIT mutation in not only exon 11 but also secondary kIT mutation in exon 13 (Asn655Thr).
Regorafenib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Solid tumour/cancer [3]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Disease Class: Mast cell neoplasm [3]
Resistant Disease Mast cell neoplasm [ICD-11: 2A21.1]
 Disease Info 
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D816Y (c.2446G>T)
Experimental Note Identified from the Human Clinical Data
Disease Class: Solid tumour/cancer [33]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.P551_E554delPMYE (c.1651_1662del12)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Solid tumour/cancer [33]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D816H (c.2446G>C)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Mast cell neoplasm [3]
Sensitive Disease Mast cell neoplasm [ICD-11: 2A21.1]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V560G (c.1679T>G)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Disease Class: Acute myeloid leukemia [3]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Disease Class: Gastrointestinal stromal tumor [34]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.T670I (c.2009C>T)
Experimental Note Identified from the Human Clinical Data
Disease Class: Gastrointestinal stromal tumor [33]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V560G (c.1679T>G)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Gastrointestinal stromal tumor [35]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.C788_N828 (c.2362_2484)
Experimental Note Identified from the Human Clinical Data
Disease Class: Gastrointestinal stromal tumor [35]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.R449_E514 (c.1345_1542)
Experimental Note Identified from the Human Clinical Data
Disease Class: Gastrointestinal stromal tumor [35]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.K550_G592 (c.1648_1776)
Experimental Note Identified from the Human Clinical Data
Disease Class: Gastrointestinal stromal tumor [35]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.P627_G664 (c.1879_1992)
Experimental Note Identified from the Human Clinical Data
Disease Class: Gastrointestinal stromal tumor [35]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.G664_C714 (c.1990_2142)
Experimental Note Identified from the Human Clinical Data
Disease Class: Gastrointestinal stromal tumor [36]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.K550_G592 (c.1648_1774)
Experimental Note Identified from the Human Clinical Data
Disease Class: Gastrointestinal stromal tumor [34]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V654A (c.1961T>C)
Experimental Note Identified from the Human Clinical Data
Disease Class: Solid tumour/cancer [33]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.P551_K558delPMYEVQWK (c.1650_1673del24)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Solid tumour/cancer [33]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.W557_K558delWK (c.1669_1674delTGGAAG)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Solid tumour/cancer [33]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Complex-indel
p.K558_558delinsNP (c.1672_1674delinsAACCCT)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Solid tumour/cancer [33]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V560D (c.1679T>A)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Gastrointestinal stromal tumor [33]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.K558_V559delKV (c.1672_1677delAAGGTT)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Gastrointestinal stromal tumor [33]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Complex-indel
p.K558delinsNP (c.1674delinsTCCT)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Gastrointestinal stromal tumor [33]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V559D (c.1676T>A)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Gastrointestinal stromal tumor [33]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration IF-deletion
p.V560_L576del17 (c.1678_1728del51)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Gastrointestinal stromal tumor [33]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V560D (c.1679T>A)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
GIST-derived cells N.A. . N.A.
In Vivo Model Female CB.17/SCID mouse xenograft model; female NOD/SCID mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis; Crystallography assay
Experiment for
Drug Resistance		 CellTiter-96 AQueous One assay
Disease Class: Gastrointestinal stromal tumor [37]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.D820Y (c.2458G>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Metastatic GI stromal tumor tissue .
Mechanism Description The missense mutation p.D820Y (c.2458G>T) in gene KIT cause the sensitivity of Regorafenib by aberration of the drug's therapeutic target
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Gastrointestinal stromal tumor [38]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Duplication
p.A502_Y503 (c.1504_1509)
Experimental Note Identified from the Human Clinical Data
In Vivo Model NOD/SCID mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Drug sensitivity test assay
Disease Class: Gastrointestinal stromal tumor [39]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Regorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.K642E (c.1924A>G)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HUVEC cells Endothelium Homo sapiens (Human) N.A.
HAoSMC cells N.A. . N.A.
In Vivo Model Female athymic NCr nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 CellTitre-Glo assay
Mechanism Description The missense mutation p.K642E (c.1924A>G) in gene KIT cause the sensitivity of Regorafenib by unusual activation of pro-survival pathway
Ripretinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Mast cell neoplasm [3]
Sensitive Disease Mast cell neoplasm [ICD-11: 2A21.1]
 Disease Info 
Sensitive Drug Ripretinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816Y (c.2446G>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Disease Class: Mast cell neoplasm [3]
Sensitive Disease Mast cell neoplasm [ICD-11: 2A21.1]
 Disease Info 
Sensitive Drug Ripretinib
 Drug Info 
Molecule Alteration Missense mutation
p.V560G (c.1679T>G)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Disease Class: Acute myeloid leukemia [3]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug Ripretinib
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Disease Class: Solid tumour/cancer [3]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Ripretinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
H1703 cells Lung Homo sapiens (Human) CVCL_1490
HCT-116 cells Colon Homo sapiens (Human) N.A.
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
HMC-1.2 cells Blood Homo sapiens (Human) CVCL_H205
P815 cells N.A. Mus musculus (Mouse) CVCL_2154
MV-4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
HMC-1.1 cells Peripheral blood Homo sapiens (Human) CVCL_H206
EOL1 cells Peripheral blood Homo sapiens (Human) CVCL_0258
CHO-K1 cells Ovary Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus) CVCL_0214
In Vivo Model Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 IC50 assay
Sunitinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Gastrointestinal stromal cancer [40]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Sunitinib
 Drug Info 
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.
Disease Class: Gastrointestinal stromal cancer [21]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Sunitinib
 Drug Info 
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.
Clinical Trial Drug(s)
5 drug(s) in total
Click to Show/Hide the Full List of Drugs
Crenolanib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Hematologic Cancer [2]
Sensitive Disease Hematologic Cancer [ICD-11: MG24.Y]
 Disease Info 
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Disease Class: Acute myeloid leukemia [2]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug Crenolanib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
MV4-11 cells Peripheral blood Homo sapiens (Human) CVCL_0064
MOLM14 cells Peripheral blood Homo sapiens (Human) CVCL_7916
In Vivo Model Female NCr-nude mouse model Mus musculus
Experiment for
Drug Resistance		 CellTiter-Glo assay; IC50 assay
Selumetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Acute myeloid leukemia [41]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug Selumetinib
 Drug Info 
Molecule Alteration Synonymous
p.L862L (c.2586G>C)
Experimental Note Identified from the Human Clinical Data
In Vitro Model Blood .
Experiment for
Molecule Alteration		 Gentra puregene assay
Experiment for
Drug Resistance		 p-ERK1/2 and p-mTOR analysis
TRAIL
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Non-small cell lung cancer [42]
Resistant Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Resistant Drug TRAIL
 Drug Info 
Molecule Alteration Expression
Down-regulation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Inhibition hsa04210
TRAIL signaling pathway Inhibition hsa04210
In Vitro Model A549 cells Lung Homo sapiens (Human) CVCL_0023
H460 cells Lung Homo sapiens (Human) CVCL_0459
Calu1 cells Lung Homo sapiens (Human) CVCL_0608
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description H460-sensitive cells treated with -221 and -222 pre-miRs become resistant to TRAIL. miR-221 and -222 target the 3'-UTR of kit and p27kip1 mRNAs, but interfere with TRAIL signaling mainly through p27kip1. miR-221 and -222 modulate TRAIL sensitivity in lung cancer cells mainly by modulating p27kip1 expression and TRAIL-induced caspase machinery.
Flumatinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Solid tumour/cancer [7]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Flumatinib
 Drug Info 
Molecule Alteration Duplication
p.I571_D579 (c.1711_1737)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 32D cells Bone marrow Homo sapiens (Human) CVCL_0118
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The duplication p.I571_D579 (c.1711_1737) in gene KIT cause the resistance of Flumatinib by aberration of the drug's therapeutic target.
Disease Class: Solid tumour/cancer [7]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Flumatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816Y (c.2446G>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model IL-3-dependent murine hematopoietic cells Blood Mus musculus (Mouse) CVCL_2015
IL-3-dependent murine hematopoietic cells Blood Mus musculus (Mouse) CVCL_2015
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Disease Class: Solid tumour/cancer [7]
Resistant Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Resistant Drug Flumatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model IL-3-dependent murine hematopoietic cells Blood Mus musculus (Mouse) CVCL_2015
IL-3-dependent murine hematopoietic cells Blood Mus musculus (Mouse) CVCL_2015
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Solid tumour/cancer [7]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Flumatinib
 Drug Info 
Molecule Alteration Complex-indel
p.T417_D419delinsI (c.1249_1257delinsATC)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 32D cells Bone marrow Homo sapiens (Human) CVCL_0118
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The complex-indel p.T417_D419delinsI (c.1249_1257delinsATC) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target.
Disease Class: Solid tumour/cancer [7]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Flumatinib
 Drug Info 
Molecule Alteration Duplication
p.A502_Y503 (c.1504_1509)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 32D cells Bone marrow Homo sapiens (Human) CVCL_0118
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The duplication p.A502_Y503 (c.1504_1509) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target.
Disease Class: Solid tumour/cancer [7]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Flumatinib
 Drug Info 
Molecule Alteration IF-deletion
p.V559_V560delVV (c.1676_1681delTTGTTG)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 32D cells Bone marrow Homo sapiens (Human) CVCL_0118
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The if-deletion p.V559_V560delVV (c.1676_1681delTTGTTG) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target.
Disease Class: Solid tumour/cancer [7]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Flumatinib
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 32D cells Bone marrow Homo sapiens (Human) CVCL_0118
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.N822K (c.2466T>G) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target
Disease Class: Solid tumour/cancer [7]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Flumatinib
 Drug Info 
Molecule Alteration Missense mutation
p.V559D (c.1676T>A)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 32D cells Bone marrow Homo sapiens (Human) CVCL_0118
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.V559D (c.1676T>A) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target
Disease Class: Solid tumour/cancer [7]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Flumatinib
 Drug Info 
Molecule Alteration Missense mutation
p.D816H (c.2446G>C)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 32D cells Bone marrow Homo sapiens (Human) CVCL_0118
In Vivo Model Female Balb/cA-nu/nu mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description The missense mutation p.D816H (c.2446G>C) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target
FF-10101
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Hematologic Cancer [43]
Sensitive Disease Hematologic Cancer [ICD-11: MG24.Y]
 Disease Info 
Sensitive Drug FF-10101
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model HEK293T cells Kidney Homo sapiens (Human) CVCL_0063
In Vivo Model NOD/SCID mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 Colony formation assay
Discontinued Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
Motesanib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Solid tumour/cancer [44]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Motesanib
 Drug Info 
Molecule Alteration IF-deletion
p.M552_V559delMYEVQWKV (c.1654_1677del24)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Mechanism Description The if-deletion p.M552_V559delMYEVQWKV (c.1654_1677del24) in gene KIT cause the sensitivity of Motesanib by aberration of the drug's therapeutic target.
Disease Class: Solid tumour/cancer [44]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Motesanib
 Drug Info 
Molecule Alteration Missense mutation
p.Y823D (c.2467T>G)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Experiment for
Molecule Alteration		 BRAF kinase assay
Mechanism Description The missense mutation p.Y823D (c.2467T>G) in gene KIT cause the sensitivity of Motesanib by aberration of the drug's therapeutic target
Disease Class: Solid tumour/cancer [44]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Motesanib
 Drug Info 
Molecule Alteration Missense mutation
p.V560D (c.1679T>A)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
Mechanism Description The missense mutation p.V560D (c.1679T>A) in gene KIT cause the sensitivity of Motesanib by aberration of the drug's therapeutic target
Tandutinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [45]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug Tandutinib
 Drug Info 
Molecule Alteration Missense mutation
p.V559D (c.1676T>A)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 ELISA assay
Mechanism Description The missense mutation p.V559D (c.1676T>A) in gene KIT cause the sensitivity of Tandutinib by unusual activation of pro-survival pathway
Preclinical Drug(s)
4 drug(s) in total
Click to Show/Hide the Full List of Drugs
BPR1J373
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [46]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug BPR1J373
 Drug Info 
Molecule Alteration Missense mutation
p.D816V (c.2447A>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
U937 cells Blood Homo sapiens (Human) CVCL_0007
K562 cells Blood Homo sapiens (Human) CVCL_0004
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
In Vivo Model SCID beige mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 WST1 assay; BD FACSCalibur assay; FACS assay
Mechanism Description BPR1J373 inhibits cell proliferation of c-KIT-driven AML cells via induction of apoptosis and cell-cycle arrest.
Disease Class: Acute myeloid leukemia [46]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Sensitive Drug BPR1J373
 Drug Info 
Molecule Alteration Missense mutation
p.N822K (c.2466T>G)
Experimental Note Identified from the Human Clinical Data
In Vitro Model KG-1 cells Bone marrow Homo sapiens (Human) CVCL_0374
THP-1 cells Blood Homo sapiens (Human) CVCL_0006
U937 cells Blood Homo sapiens (Human) CVCL_0007
K562 cells Blood Homo sapiens (Human) CVCL_0004
Kasumi-1 cells Peripheral blood Homo sapiens (Human) CVCL_0589
In Vivo Model SCID beige mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 WST1 assay; BD FACSCalibur assay; FACS assay
Mechanism Description BPR1J373 inhibits cell proliferation of c-KIT-driven AML cells via induction of apoptosis and cell-cycle arrest.
G007-LK/Imatinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Gastrointestinal stromal tumor [47]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug G007-LK/Imatinib
 Drug Info 
Molecule Alteration IF-deletion
p.V560delV (c.1679_1681delTTG)
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Wnt/Beta-catenin signaling pathway Inhibition hsa04310
In Vitro Model GIST882 cells Gastric Homo sapiens (Human) CVCL_7044
S2 GIST cells N.A. Mus musculus (Mouse) N.A.
GIST T1 cells Pleural effusion Homo sapiens (Human) CVCL_4976
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 RT-PCR; Immunohistochemistry assay; Western blotting analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Activation of the canonical Wnt pathway and accumulation of nuclear active beta-catenin were present in a subset of human GISTs that were treatment na ve, responsive to imatinib, or resistant to imatinib. The mechanism involved reduction of DKK4 and enhanced the nuclear beta-catenin stability by COP1 loss. Inhibiting Wnt/beta-catenin signaling alone or in combination with imatinib demonstrated anti-tumor efficacy in multiple cells and pre-clinical models in GIST.
Infigratinib/Imatinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Gastrointestinal stromal tumor [48]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Infigratinib/Imatinib
 Drug Info 
Molecule Alteration IF-deletion
p.V560_Y578del19 (c.1679_1735del57)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
GIST882 cells Gastric Homo sapiens (Human) CVCL_7044
In Vivo Model Athymic (nu/nu) female GIST882 xenograft mouse model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay; Colony formation assay; Real-time cell proliferation assay
Disease Class: Gastrointestinal stromal tumor [48]
Sensitive Disease Gastrointestinal stromal tumor [ICD-11: 2B5B.0]
 Disease Info 
Sensitive Drug Infigratinib/Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.K642E (c.1924A>G)
Experimental Note Identified from the Human Clinical Data
In Vitro Model GIST-T1 cells Gastric Homo sapiens (Human) CVCL_4976
GIST882 cells Gastric Homo sapiens (Human) CVCL_7044
In Vivo Model Athymic (nu/nu) female GIST882 xenograft mouse model Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 CellTiter-Glo assay; Colony formation assay; Real-time cell proliferation assay
SEL201
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Disease Class: Melanoma [49]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Sensitive Drug SEL201
 Drug Info 
Molecule Alteration Missense mutation
p.L576P (c.1727T>C)
Experimental Note Identified from the Human Clinical Data
In Vitro Model MM61 cells N.A. . N.A.
MM111 cells N.A. . N.A.
M230 cells Skin Homo sapiens (Human) CVCL_D749
LND1 cells Skin Homo sapiens (Human) CVCL_J076
HBL cells Skin Homo sapiens (Human) CVCL_J075
In Vivo Model CD-1 mouse PDX model Mus musculus
Experiment for
Drug Resistance		 SRB assay; Crystal violet staining assay; Promega assay
Mechanism Description c-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins.
Disease Class: Melanoma [49]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Sensitive Drug SEL201
 Drug Info 
Molecule Alteration Missense mutation
p.D820Y (c.2458G>T)
Experimental Note Identified from the Human Clinical Data
In Vitro Model MM61 cells N.A. . N.A.
MM111 cells N.A. . N.A.
M230 cells Skin Homo sapiens (Human) CVCL_D749
LND1 cells Skin Homo sapiens (Human) CVCL_J076
HBL cells Skin Homo sapiens (Human) CVCL_J075
In Vivo Model CD-1 mouse PDX model Mus musculus
Experiment for
Drug Resistance		 SRB assay; Crystal violet staining assay; Promega assay
Mechanism Description c-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins.
Investigative Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
Bevacizumab/Sorafenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Melanoma [50]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Sensitive Drug Bevacizumab/Sorafenib
 Drug Info 
Molecule Alteration Missense mutation
p.L576P (c.1727T>C)
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 ICH assay
Experiment for
Drug Resistance		 Radiologic assessment assay
PD-180970
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Solid tumour/cancer [45]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Sensitive Drug PD-180970
 Drug Info 
Molecule Alteration Missense mutation
p.V559D (c.1676T>A)
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK 293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 ELISA assay
Mechanism Description The missense mutation p.V559D (c.1676T>A) in gene KIT cause the sensitivity of PD-180970 by unusual activation of pro-survival pathway
Disease- and Tissue-specific Abundances of This Molecule
ICD Disease Classification 02
Click to Show/Hide the Resistance Disease of This Class
Acute myeloid leukemia [ICD-11: 2A60]
Click to Show/Hide
Differential expression of molecule in resistant diseases
The Studied Tissue Bone marrow
The Specified Disease Acute myeloid leukemia
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 9.88E-36; Fold-change: 1.65E+00; Z-score: 2.12E+00
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Lung cancer [ICD-11: 2C25]
Click to Show/Hide
Differential expression of molecule in resistant diseases
The Studied Tissue Lung
The Specified Disease Lung cancer
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 2.26E-22; Fold-change: -7.76E-01; Z-score: -1.33E+00
The Expression Level of Disease Section Compare with the Adjacent Tissue p-value: 1.80E-18; Fold-change: -9.05E-01; Z-score: -1.19E+00
Molecule expression in the normal tissue adjacent to the diseased tissue of patients
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the normal section of the tissue adjacent to the disease section
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Melanoma [ICD-11: 2C30]
Click to Show/Hide
Differential expression of molecule in resistant diseases
The Studied Tissue Skin
The Specified Disease Melanoma
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 9.21E-02; Fold-change: -4.51E-01; Z-score: -3.68E-01
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Kidney cancer [ICD-11: 2C90]
Click to Show/Hide
Differential expression of molecule in resistant diseases
The Studied Tissue Kidney
The Specified Disease Kidney cancer
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 5.94E-06; Fold-change: -1.17E+00; Z-score: -2.77E+00
The Expression Level of Disease Section Compare with the Adjacent Tissue p-value: 1.82E-13; Fold-change: -8.69E-01; Z-score: -1.40E+00
Molecule expression in the normal tissue adjacent to the diseased tissue of patients
Molecule expression in the diseased tissue of patients
Molecule expression in the normal tissue of healthy individuals
Disease-specific Molecule Abundances Click to View the Clearer Original Diagram
Download Molecule expression barchart for all samples
Download Molecule expression data of patients in the normal section of the tissue adjacent to the disease section
Download Molecule expression data of patients in the disease section of the tissue
Download Molecule expression data in the tissue of healthy individual
Tissue-specific Molecule Abundances in Healthy Individuals
Click to Show/Hide the Molecule Abundances
Download the Tissue-Specific Variation(s) Profile
References
Ref 1 ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KITCancer Res. 2019 Aug 15;79(16):4283-4292. doi: 10.1158/0008-5472.CAN-18-3139. Epub 2019 Jul 3.
Ref 2 Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignanciesBr J Haematol. 2019 Nov;187(4):488-501. doi: 10.1111/bjh.16092. Epub 2019 Jul 15.
Ref 3 Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA VariantsCancer Cell. 2019 May 13;35(5):738-751.e9. doi: 10.1016/j.ccell.2019.04.006.
Ref 4 Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal TumorsClin Cancer Res. 2019 Jan 15;25(2):609-618. doi: 10.1158/1078-0432.CCR-18-1858. Epub 2018 Oct 1.
Ref 5 A precision therapy against cancers driven by KIT/PDGFRA mutationsSci Transl Med. 2017 Nov 1;9(414):eaao1690. doi: 10.1126/scitranslmed.aao1690.
Ref 6 Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumorsTher Adv Med Oncol. 2019 May 17;11:1758835919849757. doi: 10.1177/1758835919849757. eCollection 2019.
Ref 7 Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutantsCancer Sci. 2014 Jan;105(1):117-25. doi: 10.1111/cas.12320. Epub 2014 Jan 4.
Ref 8 Cabozantinib Is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT MutationsMol Cancer Ther. 2016 Dec;15(12):2845-2852. doi: 10.1158/1535-7163.MCT-16-0224. Epub 2016 Oct 24.
Ref 9 MiR-34a-5p promotes the multi-drug resistance of osteosarcoma by targeting the CD117 gene. Oncotarget. 2016 May 10;7(19):28420-34. doi: 10.18632/oncotarget.8546.
Ref 10 MicroRNA-137 down-regulates KIT and inhibits small cell lung cancer cell proliferation. Biomed Pharmacother. 2014 Feb;68(1):7-12. doi: 10.1016/j.biopha.2013.12.002. Epub 2013 Dec 24.
Ref 11 Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014 Aug;11(8):473-81. doi: 10.1038/nrclinonc.2014.104. Epub 2014 Jul 1.
Ref 12 An Activating KIT Mutation Induces Crizotinib Resistance in ROS1-Positive Lung Cancer. J Thorac Oncol. 2016 Aug;11(8):1273-1281. doi: 10.1016/j.jtho.2016.04.001. Epub 2016 Apr 9.
Ref 13 Repression of c-Kit by p53 is mediated by miR-34 and is associated with reduced chemoresistance, migration and stemness. Oncotarget. 2013 Sep;4(9):1399-415. doi: 10.18632/oncotarget.1202.
Ref 14 Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005 Jun 1;11(11):4182-90. doi: 10.1158/1078-0432.CCR-04-2245.
Ref 15 Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res. 2006 Mar 15;12(6):1743-9. doi: 10.1158/1078-0432.CCR-05-1211.
Ref 16 Surgical intervention following imatinib treatment in patients with advanced gastrointestinal stromal tumors (GISTs). J Surg Oncol. 2008 Jul 1;98(1):27-33. doi: 10.1002/jso.21065.
Ref 17 Massively parallel sequencing fails to detect minor resistant subclones in tissue samples prior to tyrosine kinase inhibitor therapy. BMC Cancer. 2015 Apr 15;15:291. doi: 10.1186/s12885-015-1311-0.
Ref 18 Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008 Nov 20;26(33):5352-9. doi: 10.1200/JCO.2007.15.7461. Epub 2008 Oct 27.
Ref 19 Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol. 2008 Sep;216(1):64-74. doi: 10.1002/path.2382.
Ref 20 Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of sunitinib in Chinese patients with gastrointestinal stromal tumors. Med Oncol. 2013 Jun;30(2):522. doi: 10.1007/s12032-013-0522-y. Epub 2013 Mar 2.
Ref 21 A variant c-KIT mutation, D816H, fundamental to the sequential development of an ovarian mixed germ cell tumor and systemic mastocytosis with chronic myelomonocytic leukemia. Pediatr Blood Cancer. 2017 Apr;64(4). doi: 10.1002/pbc.26282. Epub 2016 Oct 26.
Ref 22 Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2017 Apr;56(4):303-313. doi: 10.1002/gcc.22438. Epub 2017 Jan 23.
Ref 23 Detection of KIT and PDGFRA mutations in the plasma of patients with gastrointestinal stromal tumor. Target Oncol. 2015 Dec;10(4):597-601. doi: 10.1007/s11523-015-0361-1. Epub 2015 Mar 5.
Ref 24 Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology. 2005 Feb;128(2):270-9. doi: 10.1053/j.gastro.2004.11.020.
Ref 25 Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006 Oct 10;24(29):4764-74. doi: 10.1200/JCO.2006.06.2265. Epub 2006 Sep 5.
Ref 26 Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5398-405. doi: 10.1158/1078-0432.CCR-06-0858.
Ref 27 Management of metastatic gastrointestinal stromal tumour in the Glivec era: a practical case-based approach .Intern Med J. 2006 Jun;36(6):367-77. doi: 10.1111/j.1445-5994.2006.01077.x. 10.1111/j.1445-5994.2006.01077.x
Ref 28 Molecular mechanisms of secondary imatinib resistance in patients with gastrointestinal stromal tumors. J Cancer Res Clin Oncol. 2010 Jul;136(7):1065-71. doi: 10.1007/s00432-009-0753-7. Epub 2009 Dec 31.
Ref 29 CCDC26 knockdown enhances resistance of gastrointestinal stromal tumor cells to imatinib by interacting with c-KIT. Am J Transl Res. 2018 Jan 15;10(1):274-282. eCollection 2018.
Ref 30 Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damageAnn Hematol. 2015 Feb;94(2):223-31. doi: 10.1007/s00277-014-2207-9. Epub 2014 Sep 11.
Ref 31 Efficacy and Safety of Midostaurin in Advanced Systemic MastocytosisN Engl J Med. 2016 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098.
Ref 32 Surgical resection of recurrent gastrointestinal stromal tumor after interruption of long-term nilotinib therapy. Surg Case Rep. 2016 Dec;2(1):137. doi: 10.1186/s40792-016-0266-y. Epub 2016 Nov 19.
Ref 33 Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patientsClin Cancer Res. 2014 Nov 15;20(22):5745-5755. doi: 10.1158/1078-0432.CCR-14-1397. Epub 2014 Sep 19.
Ref 34 Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trialLancet. 2006 Oct 14;368(9544):1329-38. doi: 10.1016/S0140-6736(06)69446-4.
Ref 35 U.S. Food and Drug Administration.
Ref 36 Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapyAnn Oncol. 2016 Sep;27(9):1794-9. doi: 10.1093/annonc/mdw228. Epub 2016 Jul 1.
Ref 37 Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trialJ Clin Oncol. 2012 Jul 1;30(19):2401-7. doi: 10.1200/JCO.2011.39.9394. Epub 2012 May 21.
Ref 38 Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitorsOncotarget. 2017 Sep 11;8(44):76712-76721. doi: 10.18632/oncotarget.20816. eCollection 2017 Sep 29.
Ref 39 Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activityInt J Cancer. 2011 Jul 1;129(1):245-55. doi: 10.1002/ijc.25864. Epub 2011 Apr 22.
Ref 40 Surgical intervention for imatinib and sunitinib-resistant gastrointestinal stromal tumors. Int J Clin Oncol. 2011 Dec;16(6):741-5. doi: 10.1007/s10147-011-0208-4. Epub 2011 Mar 12.
Ref 41 Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trialClin Cancer Res. 2014 Jan 15;20(2):490-8. doi: 10.1158/1078-0432.CCR-13-1311. Epub 2013 Oct 31.
Ref 42 MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene. 2008 Jun 19;27(27):3845-55. doi: 10.1038/onc.2008.6. Epub 2008 Feb 4.
Ref 43 A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutationsBlood. 2018 Jan 25;131(4):426-438. doi: 10.1182/blood-2017-05-786657. Epub 2017 Nov 29.
Ref 44 Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumorsJ Exp Clin Cancer Res. 2010 Jul 15;29(1):96. doi: 10.1186/1756-9966-29-96.
Ref 45 Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinasesProc Natl Acad Sci U S A. 2005 Aug 2;102(31):11011-6. doi: 10.1073/pnas.0504952102. Epub 2005 Jul 26.
Ref 46 BPR1J373, an Oral Multiple Tyrosine Kinase Inhibitor, Targets c-KIT for the Treatment of c-KIT-Driven Myeloid LeukemiaMol Cancer Ther. 2016 Oct;15(10):2323-2333. doi: 10.1158/1535-7163.MCT-15-1006. Epub 2016 Aug 10.
Ref 47 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.
Ref 48 FGFR-Mediated Reactivation of MAPK Signaling Attenuates Antitumor Effects of Imatinib in Gastrointestinal Stromal TumorsCancer Discov. 2015 Apr;5(4):438-51. doi: 10.1158/2159-8290.CD-14-0763. Epub 2015 Feb 11.
Ref 49 MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanomaJ Clin Invest. 2017 Nov 1;127(11):4179-4192. doi: 10.1172/JCI91258. Epub 2017 Oct 16.
Ref 50 Dual antiangiogenic inhibition: a phase I dose escalation and expansion trial targeting VEGF-A and VEGFR in patients with advanced solid tumorsInvest New Drugs. 2015 Feb;33(1):215-24. doi: 10.1007/s10637-014-0176-4. Epub 2014 Nov 4.

If you find any error in data or bug in web service, please kindly report it to Dr. Sun and Dr. Zhang.