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
3D-structure
PDB ID
2EC8
Classification
Transferase
Method
X-ray diffraction
Resolution
3.00  Å
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 with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
4 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 [ICD-11: 2B5B.0] [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)
Wild Type Structure Method: X-ray diffraction Resolution: 2.25  Å
PDB: 6HH1
Mutant Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 8PQG
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.88
TM score: 0.9084
Amino acid change:
T670I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
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
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 [ICD-11: 2A00-2F9Z] [2]
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)
Wild Type Structure Method: X-ray diffraction Resolution: 2.25  Å
PDB: 6HH1
Mutant Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 8PQG
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.88
TM score: 0.9084
Amino acid change:
T670I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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Click to Show/Hide the Structure
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
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 [ICD-11: 2B5B.1] [3], [4], [5]
Resistant Disease Gastrointestinal stromal cancer [ICD-11: 2B5B.1]
 Disease Info 
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T670I
Wild Type Structure Method: X-ray diffraction Resolution: 2.25  Å
PDB: 6HH1
Mutant Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 8PQG
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.88
TM score: 0.9084
Amino acid change:
T670I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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550
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L
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Y
Y
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D
580
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H
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E
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R
R
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L
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F
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610
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L
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K
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A
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630
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H
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640
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S
S
Y
Y
L
L
G
G
N
N
650
|
H
H
M
E
N
N
I
I
V
V
N
N
L
L
L
L
G
G
A
A
660
|
C
C
T
T
I
H
G
G
G
G
P
P
T
T
L
L
V
V
I
I
670
|
T
I
E
E
Y
Y
C
C
C
C
Y
Y
G
G
D
D
L
L
L
L
680
|
N
N
F
F
L
L
R
R
R
R
K
K
R
R
D
D
S
E
F
F
690
|
I
V
C
P
S
Y
K
K
T
-
-
-
-
-
-
-
-
-
-
-
700
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
710
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
720
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
730
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
740
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
750
|
-
-
-
-
-
-
S
-
P
V
A
A
I
P
-
E
-
D
-
L
760
|
-
Y
E
K
L
D
A
F
L
L
D
T
L
L
E
E
D
H
L
L
770
|
L
L
S
S
F
F
S
S
Y
Y
Q
Q
V
V
A
A
K
K
G
G
780
|
M
M
A
A
F
F
L
L
A
A
S
S
K
K
N
N
C
C
I
I
790
|
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
I
I
L
L
800
|
L
L
T
T
H
H
G
G
R
N
I
I
T
T
K
K
I
I
C
C
810
|
D
D
F
F
G
G
L
L
A
A
R
R
D
D
I
I
K
K
N
N
820
|
D
D
S
S
N
N
Y
Y
V
V
V
D
K
K
G
G
N
N
A
A
830
|
R
R
L
L
P
P
V
V
K
K
W
W
M
M
A
A
P
P
E
E
840
|
S
S
I
I
F
F
N
N
C
S
V
V
Y
Y
T
T
F
F
E
E
850
|
S
S
D
D
V
V
W
W
S
S
Y
Y
G
G
I
I
F
F
L
L
860
|
W
W
E
E
L
L
F
F
S
S
L
L
G
G
S
S
S
S
P
P
870
|
Y
Y
P
P
G
G
M
M
P
P
V
V
D
D
S
S
K
K
F
F
880
|
Y
Y
K
K
M
M
I
I
K
K
E
E
G
G
F
F
R
R
M
M
890
|
L
S
S
S
P
P
E
E
H
Y
A
A
P
P
A
A
E
E
M
M
900
|
Y
Y
D
D
I
I
M
M
K
K
T
T
C
C
W
W
D
D
A
A
910
|
D
D
P
P
L
D
K
K
R
R
P
P
T
T
F
F
K
K
Q
Q
920
|
I
I
V
V
Q
Q
L
D
I
I
E
E
K
K
Q
Q
I
I
S
S
930
|
-
E
-
S
-
T
-
N
-
H
Click to Show/Hide the Structure
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.
Regorafenib
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: Gastrointestinal stromal tumor [ICD-11: 2B5B.0] [6]
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)
Wild Type Structure Method: X-ray diffraction Resolution: 2.25  Å
PDB: 6HH1
Mutant Type Structure Method: X-ray diffraction Resolution: 2.40  Å
PDB: 8PQG
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.88
TM score: 0.9084
Amino acid change:
T670I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
-
S
550
|
-
M
-
P
-
M
-
Y
-
E
-
V
-
Q
-
W
-
K
-
V
560
|
-
V
-
E
-
E
-
S
-
N
G
G
N
N
N
N
Y
Y
V
S
570
|
Y
Y
I
I
D
D
P
P
T
T
Q
Q
L
L
P
P
Y
Y
D
D
580
|
H
H
K
K
W
W
E
E
F
F
P
P
R
R
N
N
R
R
L
L
590
|
S
S
F
F
G
G
K
K
T
T
L
L
G
G
A
A
G
G
A
A
600
|
F
F
G
G
K
K
V
V
V
V
E
E
A
A
T
T
A
A
Y
Q
610
|
G
G
L
L
I
I
K
K
S
S
D
D
A
A
A
A
M
M
T
T
620
|
V
V
A
A
V
V
K
K
M
M
L
L
K
K
P
P
S
S
A
A
630
|
H
H
L
S
T
T
E
E
R
R
E
E
A
A
L
L
M
M
S
S
640
|
E
E
L
L
K
K
V
V
L
L
S
S
Y
Y
L
L
G
G
N
N
650
|
H
H
M
E
N
N
I
I
V
V
N
N
L
L
L
L
G
G
A
A
660
|
C
C
T
T
I
H
G
G
G
G
P
P
T
T
L
L
V
V
I
I
670
|
T
I
E
E
Y
Y
C
C
C
C
Y
Y
G
G
D
D
L
L
L
L
680
|
N
N
F
F
L
L
R
R
R
R
K
K
R
R
D
D
S
E
F
F
690
|
I
V
C
P
S
Y
K
K
T
-
-
-
-
-
-
-
-
-
-
-
700
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
710
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
720
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
730
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
740
|
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
750
|
-
-
-
-
-
-
S
-
P
V
A
A
I
P
-
E
-
D
-
L
760
|
-
Y
E
K
L
D
A
F
L
L
D
T
L
L
E
E
D
H
L
L
770
|
L
L
S
S
F
F
S
S
Y
Y
Q
Q
V
V
A
A
K
K
G
G
780
|
M
M
A
A
F
F
L
L
A
A
S
S
K
K
N
N
C
C
I
I
790
|
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
I
I
L
L
800
|
L
L
T
T
H
H
G
G
R
N
I
I
T
T
K
K
I
I
C
C
810
|
D
D
F
F
G
G
L
L
A
A
R
R
D
D
I
I
K
K
N
N
820
|
D
D
S
S
N
N
Y
Y
V
V
V
D
K
K
G
G
N
N
A
A
830
|
R
R
L
L
P
P
V
V
K
K
W
W
M
M
A
A
P
P
E
E
840
|
S
S
I
I
F
F
N
N
C
S
V
V
Y
Y
T
T
F
F
E
E
850
|
S
S
D
D
V
V
W
W
S
S
Y
Y
G
G
I
I
F
F
L
L
860
|
W
W
E
E
L
L
F
F
S
S
L
L
G
G
S
S
S
S
P
P
870
|
Y
Y
P
P
G
G
M
M
P
P
V
V
D
D
S
S
K
K
F
F
880
|
Y
Y
K
K
M
M
I
I
K
K
E
E
G
G
F
F
R
R
M
M
890
|
L
S
S
S
P
P
E
E
H
Y
A
A
P
P
A
A
E
E
M
M
900
|
Y
Y
D
D
I
I
M
M
K
K
T
T
C
C
W
W
D
D
A
A
910
|
D
D
P
P
L
D
K
K
R
R
P
P
T
T
F
F
K
K
Q
Q
920
|
I
I
V
V
Q
Q
L
D
I
I
E
E
K
K
Q
Q
I
I
S
S
930
|
-
E
-
S
-
T
-
N
-
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
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 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 3 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 4 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 5 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 6 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.

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