Molecule Information

General Information of the Molecule (ID: Mol00225)
Name
Androgen receptor (AR) ,Homo sapiens
Synonyms
Dihydrotestosterone receptor; Nuclear receptor subfamily 3 group C member 4; DHTR; NR3C4
    Click to Show/Hide
Molecule Type
Protein
Gene Name
AR
Gene ID
367
Location
chrX:67544021-67730619[+]
Sequence
MEVQLGLGRVYPRPPSKTYRGAFQNLFQSVREVIQNPGPRHPEAASAAPPGASLLLLQQQ
QQQQQQQQQQQQQQQQQQQQETSPRQQQQQQGEDGSPQAHRRGPTGYLVLDEEQQPSQPQ
SALECHPERGCVPEPGAAVAASKGLPQQLPAPPDEDDSAAPSTLSLLGPTFPGLSSCSAD
LKDILSEASTMQLLQQQQQEAVSEGSSSGRAREASGAPTSSKDNYLGGTSTISDNAKELC
KAVSVSMGLGVEALEHLSPGEQLRGDCMYAPLLGVPPAVRPTPCAPLAECKGSLLDDSAG
KSTEDTAEYSPFKGGYTKGLEGESLGCSGSAAAGSSGTLELPSTLSLYKSGALDEAAAYQ
SRDYYNFPLALAGPPPPPPPPHPHARIKLENPLDYGSAWAAAAAQCRYGDLASLHGAGAA
GPGSGSPSAAASSSWHTLFTAEEGQLYGPCGGGGGGGGGGGGGGGGGGGGGGGEAGAVAP
YGYTRPPQGLAGQESDFTAPDVWYPGGMVSRVPYPSPTCVKSEMGPWMDSYSGPYGDMRL
ETARDHVLPIDYYFPPQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRN
DCTIDKFRRKNCPSCRLRKCYEAGMTLGARKLKKLGNLKLQEEGEASSTTSPTEETTQKL
TVSHIEGYECQPIFLNVLEAIEPGVVCAGHDNNQPDSFAALLSSLNELGERQLVHVVKWA
KALPGFRNLHVDDQMAVIQYSWMGLMVFAMGWRSFTNVNSRMLYFAPDLVFNEYRMHKSR
MYSQCVRMRHLSQEFGWLQITPQEFLCMKALLLFSIIPVDGLKNQKFFDELRMNYIKELD
RIIACKRKNPTSCSRRFYQLTKLLDSVQPIARELHQFTFDLLIKSHMVSVDFPEMMAEII
SVQVPKILSGKVKPIYFHTQ
    Click to Show/Hide
3D-structure
PDB ID
5CJ6
Classification
Signaling protein
Method
X-ray diffraction
Resolution
2.07  Å
Function
Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins like ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation. Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
    Click to Show/Hide
Uniprot ID
ANDR_HUMAN
Ensembl ID
ENSG00000169083
HGNC ID
HGNC:644
        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
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
7 drug(s) in total
Click to Show/Hide the Full List of Drugs
Abiraterone
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: Prostate cancer [ICD-11: 2C82.0] [1]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Abiraterone
 Drug Info 
Molecule Alteration Structural variation
Copy number gain
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole genome sequencing assay; Exome sequencing assay
Mechanism Description Accordingly, AR amplification was detected in circulating cell-free DNA and was shown to be associated with enzalutamide and abiraterone treatment resistance in a cohort of 62 CRPC patients.
Disease Class: Primary prostate cancer [ICD-11: 2C82.Z] [1]
Resistant Disease Primary prostate cancer [ICD-11: 2C82.Z]
 Disease Info 
Resistant Drug Abiraterone
 Drug Info 
Molecule Alteration Structural variation
Copy number gain
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole genome sequencing assay; Exome sequencing assay
Mechanism Description Accordingly, AR amplification was detected in circulating cell-free DNA and was shown to be associated with enzalutamide and abiraterone treatment resistance in a cohort of 62 CRPC patients.
Apalutamide
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: Prostate cancer [ICD-11: 2C82.0] [2]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Apalutamide
 Drug Info 
Molecule Alteration Missense mutation
p.F877L (c.2629T>C)
Wild Type Structure Method: X-ray diffraction Resolution: 1.44  Å
PDB: 5V8Q
Mutant Type Structure Method: X-ray diffraction Resolution: 1.69  Å
PDB: 8FH1
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.7
TM score: 0.99191
Amino acid change:
F877L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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670
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-
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L
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680
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I
A
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690
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S
A
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A
A
700
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L
A
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710
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720
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A
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L
730
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V
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D
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D
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D
M
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A
M
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A
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740
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M
L
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M
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750
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G
M
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N
760
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M
R
L
M
Y
L
F
Y
A
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A
D
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770
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F
V
N
F
E
N
Y
E
R
Y
M
R
H
M
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H
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R
S
780
|
M
R
Y
M
S
Y
Q
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C
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V
C
R
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M
R
R
M
H
R
790
|
L
H
S
L
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E
Q
F
E
G
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W
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W
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800
|
T
I
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E
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C
L
M
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M
A
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810
|
L
A
L
L
L
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F
L
S
F
I
S
I
I
P
I
V
P
D
V
820
|
G
D
L
G
K
L
N
K
Q
N
K
Q
F
K
F
F
D
F
E
D
830
|
L
E
R
L
M
R
N
M
Y
N
I
Y
K
I
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E
D
L
840
|
R
D
I
R
I
I
A
I
C
A
A
C
R
K
K
R
N
K
P
N
850
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T
P
S
T
C
S
S
C
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S
R
R
F
R
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F
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Y
L
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860
|
T
L
K
T
L
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L
L
D
L
S
D
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Q
I
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870
|
A
I
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A
E
R
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E
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L
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T
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A
D
F
880
|
L
D
L
L
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M
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V
M
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V
V
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890
|
D
V
F
D
P
F
E
P
M
E
M
M
A
M
E
A
I
E
I
I
900
|
S
I
V
S
Q
V
V
Q
P
V
K
P
I
K
L
I
S
L
G
S
910
|
K
G
V
K
K
V
P
K
I
P
Y
I
F
Y
H
F
T
H
Q
T
920
|
-
Q
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model LNCaP cells Prostate Homo sapiens (Human) CVCL_0395
PC3 cells Prostate Homo sapiens (Human) CVCL_0035
In Vivo Model SHO male mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Chromatin immunoprecipitation assay
Mechanism Description The missense mutation p.F877L (c.2629T>C) in gene AR cause the resistance of Apalutamide by aberration of the drug's therapeutic target
Disease Class: Prostate cancer [ICD-11: 2C82.0] [2]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Apalutamide
 Drug Info 
Molecule Alteration Missense mutation
p.F877L (c.2629T>C)
Wild Type Structure Method: X-ray diffraction Resolution: 1.44  Å
PDB: 5V8Q
Mutant Type Structure Method: X-ray diffraction Resolution: 1.69  Å
PDB: 8FH1
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.7
TM score: 0.99191
Amino acid change:
F877L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
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S
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H
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I
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E
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G
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Y
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670
|
-
C
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P
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I
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F
N
L
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N
L
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L
A
E
680
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I
A
E
I
P
E
G
P
V
G
V
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C
V
A
C
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A
H
G
690
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D
H
N
D
N
N
Q
N
P
Q
D
P
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D
F
S
A
F
A
A
700
|
L
A
L
L
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L
S
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S
N
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E
N
L
E
G
L
E
G
710
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R
E
Q
R
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Q
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L
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V
V
H
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V
W
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A
W
720
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K
A
A
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A
P
L
G
P
F
G
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F
N
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730
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V
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D
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D
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A
M
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740
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M
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G
M
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750
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G
M
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G
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W
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N
760
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S
M
R
L
M
Y
L
F
Y
A
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770
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F
V
N
F
E
N
Y
E
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Y
M
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S
780
|
M
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Y
M
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790
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800
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810
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L
A
L
L
L
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F
L
S
F
I
S
I
I
P
I
V
P
D
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820
|
G
D
L
G
K
L
N
K
Q
N
K
Q
F
K
F
F
D
F
E
D
830
|
L
E
R
L
M
R
N
M
Y
N
I
Y
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E
D
L
840
|
R
D
I
R
I
I
A
I
C
A
A
C
R
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K
R
N
K
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N
850
|
T
P
S
T
C
S
S
C
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S
R
R
F
R
Y
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Y
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860
|
T
L
K
T
L
K
L
L
D
L
S
D
V
S
Q
V
P
Q
I
P
870
|
A
I
R
A
E
R
L
E
H
L
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H
F
Q
T
L
F
A
D
F
880
|
L
D
L
L
I
L
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I
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K
H
S
M
H
V
M
S
V
V
S
890
|
D
V
F
D
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F
E
P
M
E
M
M
A
M
E
A
I
E
I
I
900
|
S
I
V
S
Q
V
V
Q
P
V
K
P
I
K
L
I
S
L
G
S
910
|
K
G
V
K
K
V
P
K
I
P
Y
I
F
Y
H
F
T
H
Q
T
920
|
-
Q
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model LNCaP cells Prostate Homo sapiens (Human) CVCL_0395
PC3 cells Prostate Homo sapiens (Human) CVCL_0035
In Vivo Model SHO male mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Chromatin immunoprecipitation assay
Mechanism Description The missense mutation p.F877L (c.2629T>C) in gene AR cause the resistance of Apalutamide by aberration of the drug's therapeutic target
Disease Class: Prostate cancer [ICD-11: 2C82.0] [2]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Apalutamide
 Drug Info 
Molecule Alteration Missense mutation
p.F877L (.
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model LNCaP cells Prostate Homo sapiens (Human) CVCL_0395
PC3 cells Prostate Homo sapiens (Human) CVCL_0035
In Vivo Model SHO male mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Chromatin immunoprecipitation assay
Mechanism Description The missense mutation p.F877L (. in gene AR cause the resistance of Apalutamide by aberration of the drug's therapeutic target
Bicalutamide
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: Prostate cancer [ICD-11: 2C82.0] [3]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Bicalutamide
 Drug Info 
Molecule Alteration Missense mutation
p.W742L (c.2225G>T)
Wild Type Structure Method: X-ray diffraction Resolution: 2.07  Å
PDB: 5CJ6
Mutant Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 2AX8
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.43
TM score: 0.99443
Amino acid change:
W742L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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640
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660
|
L
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E
E
G
G
Y
Y
E
E
670
|
C
C
Q
Q
P
P
I
I
F
F
L
L
N
N
V
V
L
L
E
E
680
|
A
A
I
I
E
E
P
P
G
G
V
V
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V
C
C
A
A
G
G
690
|
H
H
D
D
N
N
N
N
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Q
P
P
D
D
S
S
F
F
A
A
700
|
A
A
L
L
L
L
S
S
S
S
L
L
N
N
E
E
L
L
G
G
710
|
E
E
R
R
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Q
L
L
V
V
H
H
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V
V
V
K
K
W
W
720
|
A
A
K
K
A
A
L
L
P
P
G
G
F
F
R
R
N
N
L
L
730
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H
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V
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D
D
D
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Q
M
M
A
A
V
V
I
I
Q
Q
740
|
Y
Y
S
S
W
L
M
M
G
G
L
L
M
M
V
V
F
F
A
A
750
|
M
M
G
G
W
W
R
R
S
S
F
F
T
T
N
N
V
V
N
N
760
|
S
S
R
R
M
M
L
L
Y
Y
F
F
A
A
P
P
D
D
L
L
770
|
V
V
F
F
N
N
E
E
Y
Y
R
R
M
M
H
H
K
K
S
S
780
|
R
R
M
M
Y
Y
S
S
Q
Q
C
C
V
V
R
R
M
M
R
R
790
|
H
H
L
L
S
S
Q
Q
E
E
F
F
G
G
W
W
L
L
Q
Q
800
|
I
I
T
T
P
P
Q
Q
E
E
F
F
L
L
C
C
M
M
K
K
810
|
A
A
L
L
L
L
L
L
F
F
S
S
I
I
I
I
P
P
V
V
820
|
D
D
G
G
L
L
K
K
N
N
Q
Q
K
K
F
F
F
F
D
D
830
|
E
E
L
L
R
R
M
M
N
N
Y
Y
I
I
K
K
E
E
L
L
840
|
D
D
R
R
I
I
I
I
A
A
C
C
K
K
R
R
K
K
N
N
850
|
P
P
T
T
S
S
C
C
S
S
R
R
R
R
F
F
Y
Y
Q
Q
860
|
L
L
T
T
K
K
L
L
L
L
D
D
S
S
V
V
Q
Q
P
P
870
|
I
I
A
A
R
R
E
E
L
L
H
H
Q
Q
F
F
T
T
F
F
880
|
D
D
L
L
L
L
I
I
K
K
S
S
H
H
M
M
V
V
S
S
890
|
V
V
D
D
F
F
P
P
E
E
M
M
M
M
A
A
E
E
I
I
900
|
I
I
S
S
V
V
Q
Q
V
V
P
P
K
K
I
I
L
L
S
S
910
|
G
G
K
K
V
V
K
K
P
P
I
I
Y
Y
F
F
H
H
T
T
920
|
Q
Q
E
-
G
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Disease Class: Prostate cancer [ICD-11: 2C82.0] [3]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Bicalutamide
 Drug Info 
Molecule Alteration Missense mutation
p.W742C (c.2226G>T)
Experimental Note Identified from the Human Clinical Data
Bromocriptine
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: Prolactinomas [ICD-11: 2F37.2] [4]
Resistant Disease Prolactinomas [ICD-11: 2F37.2]
 Disease Info 
Resistant Drug Bromocriptine
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model GH3 cells Pituitary gland Rattus norvegicus (Rat) CVCL_0273
MMQ cells Pituitary gland Rattus norvegicus (Rat) CVCL_2117
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 Cell viability assay
Mechanism Description AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas.?Antioxid. Redox Signal.
Enzalutamide
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Prostate cancer [ICD-11: 2C82.0] [1]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Enzalutamide
 Drug Info 
Molecule Alteration Structural variation
Copy number gain
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole genome sequencing assay; Exome sequencing assay
Mechanism Description Accordingly, AR amplification was detected in circulating cell-free DNA and was shown to be associated with enzalutamide and abiraterone treatment resistance in a cohort of 62 CRPC patients.
Disease Class: Primary prostate cancer [ICD-11: 2C82.Z] [1]
Resistant Disease Primary prostate cancer [ICD-11: 2C82.Z]
 Disease Info 
Resistant Drug Enzalutamide
 Drug Info 
Molecule Alteration Structural variation
Copy number gain
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole genome sequencing assay; Exome sequencing assay
Mechanism Description Accordingly, AR amplification was detected in circulating cell-free DNA and was shown to be associated with enzalutamide and abiraterone treatment resistance in a cohort of 62 CRPC patients.
Flutamide
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: Prostate cancer [ICD-11: 2C82.0] [5]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Flutamide
 Drug Info 
Molecule Alteration Missense mutation
p.T878A (c.2632A>G)
Wild Type Structure Method: X-ray diffraction Resolution: 1.44  Å
PDB: 5V8Q
Mutant Type Structure Method: X-ray diffraction Resolution: 1.20  Å
PDB: 8E1A
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.92
TM score: 0.98421
Amino acid change:
T878A
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
G
-
S
-
S
-
H
-
H
650
|
-
H
-
H
-
H
-
H
-
S
-
S
-
G
-
L
-
V
-
P
660
|
-
R
-
G
-
S
-
H
-
M
-
I
-
E
-
G
-
Y
-
E
670
|
-
C
-
Q
P
P
I
I
F
F
L
L
N
N
V
V
L
L
E
E
680
|
A
A
I
I
E
E
P
P
G
G
V
V
V
V
C
C
A
A
G
G
690
|
H
H
D
D
N
N
N
N
Q
Q
P
P
D
D
S
S
F
F
A
A
700
|
A
A
L
L
L
L
S
S
S
S
L
L
N
N
E
E
L
L
G
G
710
|
E
E
R
R
Q
Q
L
L
V
V
H
H
V
V
V
V
K
K
W
W
720
|
A
A
K
K
A
A
L
L
P
P
G
G
F
F
R
R
N
N
L
L
730
|
H
H
V
V
D
D
D
D
Q
Q
M
M
A
A
V
V
I
I
Q
Q
740
|
Y
Y
S
S
W
W
M
M
G
G
L
L
M
M
V
V
F
F
A
A
750
|
M
M
G
G
W
W
R
R
S
S
F
F
T
T
N
N
V
V
N
N
760
|
S
S
R
R
M
M
L
L
Y
Y
F
F
A
A
P
P
D
D
L
L
770
|
V
V
F
F
N
N
E
E
Y
Y
R
R
M
M
H
H
K
K
S
S
780
|
R
R
M
M
Y
Y
S
S
Q
Q
C
C
V
V
R
R
M
M
R
R
790
|
H
H
L
L
S
S
Q
Q
E
E
F
F
G
G
W
W
L
L
Q
Q
800
|
I
I
T
T
P
P
Q
Q
E
E
F
F
L
L
C
C
M
M
K
K
810
|
A
A
L
L
L
L
L
L
F
F
S
S
I
I
I
I
P
P
V
V
820
|
D
D
G
G
L
L
K
K
N
N
Q
Q
K
K
F
F
F
F
D
D
830
|
E
E
L
L
R
R
M
M
N
N
Y
Y
I
I
K
K
E
E
L
L
840
|
D
D
R
R
I
I
I
I
A
A
C
C
A
K
R
R
K
K
N
N
850
|
P
P
T
T
S
S
C
C
S
S
R
R
R
R
F
F
Y
Y
Q
Q
860
|
L
L
T
T
K
K
L
L
L
L
D
D
S
S
V
V
Q
Q
P
P
870
|
I
I
A
A
R
R
E
E
L
L
H
H
Q
Q
F
F
T
A
F
F
880
|
D
D
L
L
L
L
I
I
K
K
S
S
H
H
M
M
V
V
S
S
890
|
V
V
D
D
F
F
P
P
E
E
M
M
M
M
A
A
E
E
I
I
900
|
I
I
S
S
V
V
Q
Q
V
V
P
P
K
K
I
I
L
L
S
S
910
|
G
G
K
K
V
V
K
K
P
P
I
I
Y
Y
F
F
H
H
T
T
920
|
Q
Q
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Disease Class: Prostate cancer [ICD-11: 2C82.0] [5]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Flutamide
 Drug Info 
Molecule Alteration Missense mutation
p.T877A
Experimental Note Identified from the Human Clinical Data
Disease Class: Prostate cancer [ICD-11: 2C82.0] [6]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Flutamide
 Drug Info 
Molecule Alteration Expression
Up-regulation
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model LN-FLU cells Prostate Homo sapiens (Human) N.A.
Experiment for
Molecule Alteration		 Western blot assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description To obtain molecular evidence of the acquired resistance of the LN-FLU cells, we checked the expressions of significant proteins involved in prostate cell growth. As shown in, the LN-FLU cells showed less expression of the androgen receptor (AR) compared with the parental LNCaP cells, further confirming the androgen refractory state of the cells.
Hydroxyflutamide
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Disease Class: Prostate cancer [ICD-11: 2C82.0] [7]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Hydroxyflutamide
 Drug Info 
Molecule Alteration Missense mutation
p.T877A
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Energy decomposition assay
Mechanism Description However, a drug resistance problem appears after about one year's treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot.
Disease Class: Prostate cancer [ICD-11: 2C82.0] [7]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Hydroxyflutamide
 Drug Info 
Molecule Alteration Missense mutation+Missense mutation
p.W741C+T877
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Energy decomposition assay
Mechanism Description However, a drug resistance problem appears after about one year's treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot.
Disease Class: Prostate cancer [ICD-11: 2C82.0] [7]
Resistant Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Resistant Drug Hydroxyflutamide
 Drug Info 
Molecule Alteration Missense mutation+Missense mutation
p.F876L+T877A
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Energy decomposition assay
Mechanism Description However, a drug resistance problem appears after about one year's treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot.
Clinical Trial Drug(s)
2 drug(s) in total
Click to Show/Hide the Full List of Drugs
Capivasertib
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Disease Class: Prostate cancer [ICD-11: 2C82.0] [8]
Sensitive Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Sensitive Drug Capivasertib
 Drug Info 
Molecule Alteration Function
Activation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model LNCaP clone FGC cells N.A. Homo sapiens (Human) CVCL_1379
22Rv-1 cells Prostate Homo sapiens (Human) CVCL_1045
Experiment for
Molecule Alteration		 Cell protein extraction assay; Western blot assay; qRT-PCR; Luciferase reporter assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the beta-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.
LY-294002
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: Prostate cancer [ICD-11: 2C82.0] [8]
Sensitive Disease Prostate cancer [ICD-11: 2C82.0]
 Disease Info 
Sensitive Drug LY-294002
 Drug Info 
Molecule Alteration Function
Activation
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation PI3K/AKT signaling pathway Inhibition hsa04151
In Vitro Model LNCaP clone FGC cells N.A. Homo sapiens (Human) CVCL_1379
22Rv-1 cells Prostate Homo sapiens (Human) CVCL_1045
Experiment for
Molecule Alteration		 Cell protein extraction assay; Western blot assay; qRT-PCR; Luciferase reporter assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the beta-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.
Disease- and Tissue-specific Abundances of This Molecule
ICD Disease Classification 02
Click to Show/Hide the Resistance Disease of This Class
Prostate cancer [ICD-11: 2C82]
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Differential expression of molecule in resistant diseases
The Studied Tissue Prostate
The Specified Disease Prostate cancer
The Expression Level of Disease Section Compare with the Healthy Individual Tissue p-value: 4.81E-01; Fold-change: -2.29E-01; Z-score: -2.85E-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
Tissue-specific Molecule Abundances in Healthy Individuals
Click to Show/Hide the Molecule Abundances
Download the Tissue-Specific Variation(s) Profile
References
Ref 1 Clonal origin and spread of metastatic prostate cancer. Endocr Relat Cancer. 2016 Apr;23(4):R207-17. doi: 10.1530/ERC-16-0049. Epub 2016 Mar 21.
Ref 2 A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509Cancer Discov. 2013 Sep;3(9):1020-9. doi: 10.1158/2159-8290.CD-13-0226. Epub 2013 Jun 18.
Ref 3 Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndromeCancer Res. 2003 Jan 1;63(1):149-53.
Ref 4 Androgen Receptor Mediates Dopamine Agonist Resistance by Regulating Intracellular Reactive Oxygen Species in Prolactin-Secreting Pituitary Adenoma. Antioxid Redox Signal. 2025 Jun;42(16-18):954-972.
Ref 5 A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgensBiochem Biophys Res Commun. 1990 Dec 14;173(2):534-40. doi: 10.1016/s0006-291x(05)80067-1.
Ref 6 Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of Phosphatidylcholine Biosynthesis and Epigenetic Modifications. Int J Mol Sci. 2023 Oct 26;24(21):15626.
Ref 7 A Molecular Modeling Study of the Hydroxyflutamide Resistance Mechanism Induced by Androgen Receptor Mutations .Int J Mol Sci. 2017 Aug 23;18(9):1823. doi: 10.3390/ijms18091823. 10.3390/ijms18091823
Ref 8 PI3K/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation. Biochim Biophys Acta Mol Basis Dis. 2025 Feb;1871(2):167568.

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