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
• 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
• 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.
• Uniprot ID: ANDR_HUMAN
• Ensembl ID: ENSG00000169083
• HGNC ID: HGNC:644

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) 6 drug(s) in total

Abiraterone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Prostate cancer [1]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Abiraterone
• 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 [1]

• Resistant Disease: Primary prostate cancer [ICD-11: 2C82.Z]
• Resistant Drug: Abiraterone
• 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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Prostate cancer [2]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Molecule Alteration: Missense mutation; p.F877L (c.2629T>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: 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 [2]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Molecule Alteration: Missense mutation; p.F877L (c.2629T>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: 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 [2]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• 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
• In Vitro Model: 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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Prostate cancer [3]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Bicalutamide
• Molecule Alteration: Missense mutation; p.W742L (c.2225G>T)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Prostate cancer [3]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Bicalutamide
• Molecule Alteration: Missense mutation; p.W742C (c.2226G>T)
• Experimental Note: Identified from the Human Clinical Data

Enzalutamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Prostate cancer [1]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Enzalutamide
• 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 [1]

• Resistant Disease: Primary prostate cancer [ICD-11: 2C82.Z]
• Resistant Drug: Enzalutamide
• 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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Prostate cancer [4]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Flutamide
• Molecule Alteration: Missense mutation; p.T878A (c.2632A>G)
• Experimental Note: Identified from the Human Clinical Data

Disease Class: Prostate cancer [4]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Flutamide
• Molecule Alteration: Missense mutation; p.T877A
• Experimental Note: Identified from the Human Clinical Data

Hydroxyflutamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Prostate cancer [5]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Hydroxyflutamide
• 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 [5]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Hydroxyflutamide
• 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 [5]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Hydroxyflutamide
• 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.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Prostate cancer [ICD-11: 2C82]

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

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: 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 5: 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